Jen Smith

Attendees at the 2016

ASH Annual Meeting

SAN DIEGO—Interim results of the phase 3 GALLIUM trial suggest an obinutuzumab-based treatment regimen provides a progression-free survival (PFS) benefit over a rituximab-based regimen for patients with previously untreated follicular lymphoma (FL).

According to investigators, patients who received obinutuzumab plus chemotherapy followed by obinutuzumab maintenance had a “clinically meaningful” improvement in PFS, when compared to patients who received rituximab plus chemotherapy followed by rituximab maintenance.

However, there was no significant difference between the treatment arms with regard to overall survival. And the incidence of non-fatal adverse events (AEs) was higher among the patients who received obinutuzumab.

Nevertheless, the data suggest that obinutuzumab-based therapy significantly improves outcomes and should be considered as a first-line treatment for FL, according to Robert Marcus, MBBS, of King’s College Hospital in London, UK.

Dr Marcus presented data from GALLIUM during the plenary session at the 2016 ASH Annual Meeting (abstract 6). GALLIUM is sponsored by Hoffmann-La Roche.

Patients and treatment

The study has enrolled 1401 patients with previously untreated, indolent non-Hodgkin lymphoma, including 1202 with FL.

Half of the FL patients (n=601) were randomized to obinutuzumab plus chemotherapy followed by obinutuzumab alone for up to 2 years, and half were randomized to rituximab plus chemotherapy followed by rituximab alone for up to 2 years.

The different chemotherapies used were CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone), CVP (cyclophosphamide, vincristine, and prednisolone), and bendamustine. The regimens were selected by each participating study site prior to beginning enrollment.

Baseline characteristics were similar between the treatment arms. The median age was about 60 (overall range, 23-88), roughly 40% of patients had high-risk disease, and the median time from diagnosis to randomization was about 1.5 months.

A total of 341 patients in the rituximab arm and 361 patients in the obinutuzumab arm completed maintenance therapy.

The median follow-up was 34.5 months. Maintenance is ongoing in 114 patients—54 on rituximab and 60 on obinutuzumab.

Efficacy

At the end of induction, the overall response rate was 86.9% in the rituximab arm and 88.5% in the obinutuzumab arm. The complete response rates were 23.8% and 19.5%, respectively. And the rates of stable disease were 1.3% and 0.5%, respectively.

The study’s primary endpoint is investigator-assessed PFS. The 3-year PFS rate is 73.3% in the rituximab arm and 80% in the obinutuzumab arm (hazard ratio [HR]=0.66, P=0.0012).

According to an independent review committee, the 3-year PFS is 77.9% in the rituximab arm and 81.9% in the obinutuzumab arm (HR=0.71, P=0.0138).

The 3-year overall survival is 92.1% in the rituximab arm and 94% in the obinutuzumab arm (HR=0.75, P=0.21).

Safety

The overall incidence of AEs was 98.3% in the rituximab arm and 99.5% in the obinutuzumab arm. The incidence of serious AEs was 39.9% and 46.1%, respectively.

The incidence of AEs leading to treatment discontinuation was 14.2% and 16.3%, respectively. And the incidence of second neoplasms was 2.7% and 4.7%, respectively.

Grade 5 AEs occurred in 3.4% of patients in the rituximab arm and 4.0% of patients in the obinutuzumab arm. The investigators found that fatal AEs were more common in patients taking bendamustine, regardless of the treatment arm.

Grade 3 or higher AEs occurring in at least 5% of patients in either arm (rituximab and obinutuzumab, respectively) included neutropenia (67.8% and 74.6%), leukopenia (37.9% and 43.9%), febrile neutropenia (4.9% and 6.9%), infections and infestations (3.7% and 6.7%), and thrombocytopenia (2.7% and 6.1%).

Attendees at the 2016

ASH Annual Meeting

SAN DIEGO—Interim results of the phase 3 GALLIUM trial suggest an obinutuzumab-based treatment regimen provides a progression-free survival (PFS) benefit over a rituximab-based regimen for patients with previously untreated follicular lymphoma (FL).

According to investigators, patients who received obinutuzumab plus chemotherapy followed by obinutuzumab maintenance had a “clinically meaningful” improvement in PFS, when compared to patients who received rituximab plus chemotherapy followed by rituximab maintenance.

However, there was no significant difference between the treatment arms with regard to overall survival. And the incidence of non-fatal adverse events (AEs) was higher among the patients who received obinutuzumab.

Nevertheless, the data suggest that obinutuzumab-based therapy significantly improves outcomes and should be considered as a first-line treatment for FL, according to Robert Marcus, MBBS, of King’s College Hospital in London, UK.

Dr Marcus presented data from GALLIUM during the plenary session at the 2016 ASH Annual Meeting (abstract 6). GALLIUM is sponsored by Hoffmann-La Roche.

Patients and treatment

The study has enrolled 1401 patients with previously untreated, indolent non-Hodgkin lymphoma, including 1202 with FL.

Half of the FL patients (n=601) were randomized to obinutuzumab plus chemotherapy followed by obinutuzumab alone for up to 2 years, and half were randomized to rituximab plus chemotherapy followed by rituximab alone for up to 2 years.

The different chemotherapies used were CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone), CVP (cyclophosphamide, vincristine, and prednisolone), and bendamustine. The regimens were selected by each participating study site prior to beginning enrollment.

Baseline characteristics were similar between the treatment arms. The median age was about 60 (overall range, 23-88), roughly 40% of patients had high-risk disease, and the median time from diagnosis to randomization was about 1.5 months.

A total of 341 patients in the rituximab arm and 361 patients in the obinutuzumab arm completed maintenance therapy.

The median follow-up was 34.5 months. Maintenance is ongoing in 114 patients—54 on rituximab and 60 on obinutuzumab.

Efficacy

At the end of induction, the overall response rate was 86.9% in the rituximab arm and 88.5% in the obinutuzumab arm. The complete response rates were 23.8% and 19.5%, respectively. And the rates of stable disease were 1.3% and 0.5%, respectively.

The study’s primary endpoint is investigator-assessed PFS. The 3-year PFS rate is 73.3% in the rituximab arm and 80% in the obinutuzumab arm (hazard ratio [HR]=0.66, P=0.0012).

According to an independent review committee, the 3-year PFS is 77.9% in the rituximab arm and 81.9% in the obinutuzumab arm (HR=0.71, P=0.0138).

The 3-year overall survival is 92.1% in the rituximab arm and 94% in the obinutuzumab arm (HR=0.75, P=0.21).

Safety

The overall incidence of AEs was 98.3% in the rituximab arm and 99.5% in the obinutuzumab arm. The incidence of serious AEs was 39.9% and 46.1%, respectively.

The incidence of AEs leading to treatment discontinuation was 14.2% and 16.3%, respectively. And the incidence of second neoplasms was 2.7% and 4.7%, respectively.

Grade 5 AEs occurred in 3.4% of patients in the rituximab arm and 4.0% of patients in the obinutuzumab arm. The investigators found that fatal AEs were more common in patients taking bendamustine, regardless of the treatment arm.

Grade 3 or higher AEs occurring in at least 5% of patients in either arm (rituximab and obinutuzumab, respectively) included neutropenia (67.8% and 74.6%), leukopenia (37.9% and 43.9%), febrile neutropenia (4.9% and 6.9%), infections and infestations (3.7% and 6.7%), and thrombocytopenia (2.7% and 6.1%).

Attendees at the 2016

ASH Annual Meeting

SAN DIEGO—Interim results of the phase 3 GALLIUM trial suggest an obinutuzumab-based treatment regimen provides a progression-free survival (PFS) benefit over a rituximab-based regimen for patients with previously untreated follicular lymphoma (FL).

According to investigators, patients who received obinutuzumab plus chemotherapy followed by obinutuzumab maintenance had a “clinically meaningful” improvement in PFS, when compared to patients who received rituximab plus chemotherapy followed by rituximab maintenance.

However, there was no significant difference between the treatment arms with regard to overall survival. And the incidence of non-fatal adverse events (AEs) was higher among the patients who received obinutuzumab.

Nevertheless, the data suggest that obinutuzumab-based therapy significantly improves outcomes and should be considered as a first-line treatment for FL, according to Robert Marcus, MBBS, of King’s College Hospital in London, UK.

Dr Marcus presented data from GALLIUM during the plenary session at the 2016 ASH Annual Meeting (abstract 6). GALLIUM is sponsored by Hoffmann-La Roche.

Patients and treatment

The study has enrolled 1401 patients with previously untreated, indolent non-Hodgkin lymphoma, including 1202 with FL.

Half of the FL patients (n=601) were randomized to obinutuzumab plus chemotherapy followed by obinutuzumab alone for up to 2 years, and half were randomized to rituximab plus chemotherapy followed by rituximab alone for up to 2 years.

The different chemotherapies used were CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone), CVP (cyclophosphamide, vincristine, and prednisolone), and bendamustine. The regimens were selected by each participating study site prior to beginning enrollment.

Baseline characteristics were similar between the treatment arms. The median age was about 60 (overall range, 23-88), roughly 40% of patients had high-risk disease, and the median time from diagnosis to randomization was about 1.5 months.

A total of 341 patients in the rituximab arm and 361 patients in the obinutuzumab arm completed maintenance therapy.

The median follow-up was 34.5 months. Maintenance is ongoing in 114 patients—54 on rituximab and 60 on obinutuzumab.

Efficacy

At the end of induction, the overall response rate was 86.9% in the rituximab arm and 88.5% in the obinutuzumab arm. The complete response rates were 23.8% and 19.5%, respectively. And the rates of stable disease were 1.3% and 0.5%, respectively.

The study’s primary endpoint is investigator-assessed PFS. The 3-year PFS rate is 73.3% in the rituximab arm and 80% in the obinutuzumab arm (hazard ratio [HR]=0.66, P=0.0012).

According to an independent review committee, the 3-year PFS is 77.9% in the rituximab arm and 81.9% in the obinutuzumab arm (HR=0.71, P=0.0138).

The 3-year overall survival is 92.1% in the rituximab arm and 94% in the obinutuzumab arm (HR=0.75, P=0.21).

Safety

The overall incidence of AEs was 98.3% in the rituximab arm and 99.5% in the obinutuzumab arm. The incidence of serious AEs was 39.9% and 46.1%, respectively.

The incidence of AEs leading to treatment discontinuation was 14.2% and 16.3%, respectively. And the incidence of second neoplasms was 2.7% and 4.7%, respectively.

Grade 5 AEs occurred in 3.4% of patients in the rituximab arm and 4.0% of patients in the obinutuzumab arm. The investigators found that fatal AEs were more common in patients taking bendamustine, regardless of the treatment arm.

Grade 3 or higher AEs occurring in at least 5% of patients in either arm (rituximab and obinutuzumab, respectively) included neutropenia (67.8% and 74.6%), leukopenia (37.9% and 43.9%), febrile neutropenia (4.9% and 6.9%), infections and infestations (3.7% and 6.7%), and thrombocytopenia (2.7% and 6.1%).

Uwe Platzbecker, MD

COPENHAGEN—Results from a pair of phase 2 trials suggest luspatercept can produce erythroid responses and enable transfusion independence in patients with lower-risk myelodysplastic syndromes (MDS).

In a 3-month base study, 51% of patients treated with luspatercept had an erythroid response, and 35% achieved transfusion independence.

In an ongoing extension study, 81% of luspatercept-treated patients have had an erythroid response, and 50% have achieved transfusion independence.

The majority of adverse events in both trials were grade 1 and 2.

Uwe Platzbecker, MD, of the University Hospital in Dresden, Germany, presented these results at the 21st Congress of the European Hematology Association (abstract S131*). The studies were sponsored by Acceleron Pharma, Inc.

Luspatercept (formerly ACE-536) is a modified activin receptor type IIB fusion protein that increases red blood cell (RBC) levels by targeting molecules in the TGF-β superfamily. Acceleron and Celgene are developing luspatercept to treat anemia in patients with rare blood disorders.

The phase 2 base study was a dose-escalation trial in which MDS patients received luspatercept for 3 months. In the ongoing extension study, patients from the base study are receiving luspatercept for an additional 24 months.

In both studies, patients with high transfusion burden (≥4 RBC units/8 weeks) and those with low transfusion burden (<4 RBC units/8 weeks) received luspatercept once every 3 weeks.

Base study

This study included 58 patients with a median age of 71.5 (range, 27-90). Their median time since diagnosis was 2.4 years (range, 0-14). Seventeen percent of patients had prior lenalidomide treatment, and 66% had previously received erythropoiesis-stimulating agents (ESAs).

In patients with low transfusion burden (n=19), the median hemoglobin at baseline was 8.7 g/dL (range, 6.4-10.1). In patients with high transfusion burden (n=39), the median number of RBC units transfused per 8 weeks was 6 (range, 4-18).

Patients received luspatercept subcutaneously every 3 weeks for up to 5 doses. The study included 7 dose-escalation cohorts (n=27, 0.125 to 1.75 mg/kg) and an expansion cohort (n=31, 1.0 to 1.75 mg/kg).

The primary outcome measure was the proportion of patients who had an erythroid response. In non-transfusion-dependent patients, an erythroid response was defined as a hemoglobin increase of at least 1.5 g/dL from baseline for at least 14 days.

In transfusion-dependent patients, an erythroid response was defined as a reduction of at least 4 RBC units transfused or a reduction of at least 50% of RBC units transfused compared to pretreatment.

Fifty-one percent (25/49) of patients treated at the higher dose levels had an erythroid response. And 35% (14/40) of transfused patients treated at the higher dose levels were transfusion independent for at least 8 weeks.

Extension study

This study includes 32 patients with a median age of 71.5 (range, 29-90). Their median time since diagnosis was 2.9 years (range, 0-14). Nineteen percent of patients had prior lenalidomide treatment, and 59% had previously received ESAs.

In patients with low transfusion burden (n=13), the median hemoglobin at baseline was 8.5 g/dL (range, 6.4-10.1). In patients with high transfusion burden (n=19), the median number of RBC units transfused per 8 weeks was 6 (range, 4-14).

In this ongoing study, patients are receiving luspatercept (1.0 to 1.75 mg/kg) subcutaneously every 3 weeks for an additional 24 months.

At last follow-up (March 4, 2016), 81% (26/32) of patients had an erythroid response. And 50% (11/22) of patients who were transfused prior to study initiation achieved transfusion independence for at least 8 weeks (range, 9-80+ weeks).

Dr Platzbecker noted that, in both studies, erythroid responses were observed whether or not patients previously received ESAs and regardless of patients’ baseline erythropoietin levels.

Safety

There were three grade 3 adverse events that were possibly or probably related to luspatercept—an increase in blast cell count, myalgia, and worsening of general condition.

Adverse events that were possibly or probably related to luspatercept and occurred in at least 2 patients were fatigue (7%, n=4), bone pain (5%, n=3), diarrhea (5%, n=3), myalgia (5%, n=3), headache (3%, n=2), hypertension (3%, n=2), and injection site erythema (3%, n=2).

Dr Platzbecker said luspatercept was generally safe and well-tolerated in these studies. And the results of these trials supported the initiation of a phase 3 study (MEDALIST, NCT02631070) in patients with lower-risk MDS.

*Data in the abstract differ from data presented at the meeting.

Uwe Platzbecker, MD

COPENHAGEN—Results from a pair of phase 2 trials suggest luspatercept can produce erythroid responses and enable transfusion independence in patients with lower-risk myelodysplastic syndromes (MDS).

In a 3-month base study, 51% of patients treated with luspatercept had an erythroid response, and 35% achieved transfusion independence.

In an ongoing extension study, 81% of luspatercept-treated patients have had an erythroid response, and 50% have achieved transfusion independence.

The majority of adverse events in both trials were grade 1 and 2.

Uwe Platzbecker, MD, of the University Hospital in Dresden, Germany, presented these results at the 21st Congress of the European Hematology Association (abstract S131*). The studies were sponsored by Acceleron Pharma, Inc.

Luspatercept (formerly ACE-536) is a modified activin receptor type IIB fusion protein that increases red blood cell (RBC) levels by targeting molecules in the TGF-β superfamily. Acceleron and Celgene are developing luspatercept to treat anemia in patients with rare blood disorders.

The phase 2 base study was a dose-escalation trial in which MDS patients received luspatercept for 3 months. In the ongoing extension study, patients from the base study are receiving luspatercept for an additional 24 months.

In both studies, patients with high transfusion burden (≥4 RBC units/8 weeks) and those with low transfusion burden (<4 RBC units/8 weeks) received luspatercept once every 3 weeks.

Base study

This study included 58 patients with a median age of 71.5 (range, 27-90). Their median time since diagnosis was 2.4 years (range, 0-14). Seventeen percent of patients had prior lenalidomide treatment, and 66% had previously received erythropoiesis-stimulating agents (ESAs).

In patients with low transfusion burden (n=19), the median hemoglobin at baseline was 8.7 g/dL (range, 6.4-10.1). In patients with high transfusion burden (n=39), the median number of RBC units transfused per 8 weeks was 6 (range, 4-18).

Patients received luspatercept subcutaneously every 3 weeks for up to 5 doses. The study included 7 dose-escalation cohorts (n=27, 0.125 to 1.75 mg/kg) and an expansion cohort (n=31, 1.0 to 1.75 mg/kg).

The primary outcome measure was the proportion of patients who had an erythroid response. In non-transfusion-dependent patients, an erythroid response was defined as a hemoglobin increase of at least 1.5 g/dL from baseline for at least 14 days.

In transfusion-dependent patients, an erythroid response was defined as a reduction of at least 4 RBC units transfused or a reduction of at least 50% of RBC units transfused compared to pretreatment.

Fifty-one percent (25/49) of patients treated at the higher dose levels had an erythroid response. And 35% (14/40) of transfused patients treated at the higher dose levels were transfusion independent for at least 8 weeks.

Extension study

This study includes 32 patients with a median age of 71.5 (range, 29-90). Their median time since diagnosis was 2.9 years (range, 0-14). Nineteen percent of patients had prior lenalidomide treatment, and 59% had previously received ESAs.

In patients with low transfusion burden (n=13), the median hemoglobin at baseline was 8.5 g/dL (range, 6.4-10.1). In patients with high transfusion burden (n=19), the median number of RBC units transfused per 8 weeks was 6 (range, 4-14).

In this ongoing study, patients are receiving luspatercept (1.0 to 1.75 mg/kg) subcutaneously every 3 weeks for an additional 24 months.

At last follow-up (March 4, 2016), 81% (26/32) of patients had an erythroid response. And 50% (11/22) of patients who were transfused prior to study initiation achieved transfusion independence for at least 8 weeks (range, 9-80+ weeks).

Dr Platzbecker noted that, in both studies, erythroid responses were observed whether or not patients previously received ESAs and regardless of patients’ baseline erythropoietin levels.

Safety

There were three grade 3 adverse events that were possibly or probably related to luspatercept—an increase in blast cell count, myalgia, and worsening of general condition.

Adverse events that were possibly or probably related to luspatercept and occurred in at least 2 patients were fatigue (7%, n=4), bone pain (5%, n=3), diarrhea (5%, n=3), myalgia (5%, n=3), headache (3%, n=2), hypertension (3%, n=2), and injection site erythema (3%, n=2).

Dr Platzbecker said luspatercept was generally safe and well-tolerated in these studies. And the results of these trials supported the initiation of a phase 3 study (MEDALIST, NCT02631070) in patients with lower-risk MDS.

*Data in the abstract differ from data presented at the meeting.

Uwe Platzbecker, MD

COPENHAGEN—Results from a pair of phase 2 trials suggest luspatercept can produce erythroid responses and enable transfusion independence in patients with lower-risk myelodysplastic syndromes (MDS).

In a 3-month base study, 51% of patients treated with luspatercept had an erythroid response, and 35% achieved transfusion independence.

In an ongoing extension study, 81% of luspatercept-treated patients have had an erythroid response, and 50% have achieved transfusion independence.

The majority of adverse events in both trials were grade 1 and 2.

Uwe Platzbecker, MD, of the University Hospital in Dresden, Germany, presented these results at the 21st Congress of the European Hematology Association (abstract S131*). The studies were sponsored by Acceleron Pharma, Inc.

Luspatercept (formerly ACE-536) is a modified activin receptor type IIB fusion protein that increases red blood cell (RBC) levels by targeting molecules in the TGF-β superfamily. Acceleron and Celgene are developing luspatercept to treat anemia in patients with rare blood disorders.

The phase 2 base study was a dose-escalation trial in which MDS patients received luspatercept for 3 months. In the ongoing extension study, patients from the base study are receiving luspatercept for an additional 24 months.

In both studies, patients with high transfusion burden (≥4 RBC units/8 weeks) and those with low transfusion burden (<4 RBC units/8 weeks) received luspatercept once every 3 weeks.

Base study

This study included 58 patients with a median age of 71.5 (range, 27-90). Their median time since diagnosis was 2.4 years (range, 0-14). Seventeen percent of patients had prior lenalidomide treatment, and 66% had previously received erythropoiesis-stimulating agents (ESAs).

In patients with low transfusion burden (n=19), the median hemoglobin at baseline was 8.7 g/dL (range, 6.4-10.1). In patients with high transfusion burden (n=39), the median number of RBC units transfused per 8 weeks was 6 (range, 4-18).

Patients received luspatercept subcutaneously every 3 weeks for up to 5 doses. The study included 7 dose-escalation cohorts (n=27, 0.125 to 1.75 mg/kg) and an expansion cohort (n=31, 1.0 to 1.75 mg/kg).

The primary outcome measure was the proportion of patients who had an erythroid response. In non-transfusion-dependent patients, an erythroid response was defined as a hemoglobin increase of at least 1.5 g/dL from baseline for at least 14 days.

In transfusion-dependent patients, an erythroid response was defined as a reduction of at least 4 RBC units transfused or a reduction of at least 50% of RBC units transfused compared to pretreatment.

Fifty-one percent (25/49) of patients treated at the higher dose levels had an erythroid response. And 35% (14/40) of transfused patients treated at the higher dose levels were transfusion independent for at least 8 weeks.

Extension study

This study includes 32 patients with a median age of 71.5 (range, 29-90). Their median time since diagnosis was 2.9 years (range, 0-14). Nineteen percent of patients had prior lenalidomide treatment, and 59% had previously received ESAs.

In patients with low transfusion burden (n=13), the median hemoglobin at baseline was 8.5 g/dL (range, 6.4-10.1). In patients with high transfusion burden (n=19), the median number of RBC units transfused per 8 weeks was 6 (range, 4-14).

In this ongoing study, patients are receiving luspatercept (1.0 to 1.75 mg/kg) subcutaneously every 3 weeks for an additional 24 months.

At last follow-up (March 4, 2016), 81% (26/32) of patients had an erythroid response. And 50% (11/22) of patients who were transfused prior to study initiation achieved transfusion independence for at least 8 weeks (range, 9-80+ weeks).

Dr Platzbecker noted that, in both studies, erythroid responses were observed whether or not patients previously received ESAs and regardless of patients’ baseline erythropoietin levels.

Safety

There were three grade 3 adverse events that were possibly or probably related to luspatercept—an increase in blast cell count, myalgia, and worsening of general condition.

Adverse events that were possibly or probably related to luspatercept and occurred in at least 2 patients were fatigue (7%, n=4), bone pain (5%, n=3), diarrhea (5%, n=3), myalgia (5%, n=3), headache (3%, n=2), hypertension (3%, n=2), and injection site erythema (3%, n=2).

Dr Platzbecker said luspatercept was generally safe and well-tolerated in these studies. And the results of these trials supported the initiation of a phase 3 study (MEDALIST, NCT02631070) in patients with lower-risk MDS.

*Data in the abstract differ from data presented at the meeting.

Johan Richter, MD, PhD

COPENHAGEN—Results of a large study suggest that stopping treatment with tyrosine kinase inhibitors (TKIs) can be safe for patients with chronic myeloid leukemia (CML) in deep molecular response (MR4).

Six months after patients stopped receiving a TKI, the relapse-free survival was 62%. At 12 months, it was 56%.

Havinga longer duration of TKI treatment and a longer duration of deep molecular response were both associated with a higher likelihood of relapse-free survival.

These results, from the EURO-SKI trial, were presented at the 21st Congress of the European Hematology Association (abstract S145*) by Johan Richter, MD, PhD, of Skåne University Hospital in Lund, Sweden.

The goal of the EURO-SKI study was to define prognostic markers to increase the proportion of patients in durable deep molecular response after stopping TKI treatment.

The trial included 760 adults with chronic phase CML who were on TKI treatment for at least 3 years. Patients were either on their first TKI or on their second TKI due to toxicity with their first. (None had failed TKI treatment.)

Patients had been in MR4 (BCR/ABL <0.01%) for at least a year, which was confirmed by 3 consecutive polymerase chain reaction (PCR) results during the last 12 months. The final MR4 confirmation was performed in a EUTOS standardized laboratory.

After the final MR4 confirmation, patients stopped TKI treatment. They underwent real-time quantitative PCR (RQ-PCR) every 4 weeks for the first 6 months and every 6 weeks for the next 6 months. In years 2 and 3, they underwent RQ-PCR every third month.

The patients had a median age at diagnosis of 52 (range, 11.2-85.5) and a median age at TKI stop of 60.3 (range, 19.5-89.9). The median duration of TKI therapy was 7.6 years (range, 3.0-14.2), and the median duration of MR4 before TKI stop was 4.7 years (range, 1.0-13.3).

Most patients had received imatinib (n=710) as first-line TKI treatment, though some received nilotinib (n=35) or dasatinib (n=14). The type of first-line TKI was unknown in 1 patient. Second-line TKI treatment included imatinib (n=7), nilotinib (n=47), and dasatinib (n=57).

Relapse, survival, and safety

Six months after stopping TKI treatment, the cumulative incidence of molecular relapse was 37%. It was 43% at 12 months, 47% at 24 months, and 50% at 36 months.

In all, 347 patients had a molecular relapse. Seventy-two patients had BCR/ABL >1%, and 11 lost their complete cytogenetic response. None of the patients progressed to accelerated phase or blast crisis.

Among patients who restarted TKI treatment, the median time to restart was 4.1 months. Fourteen patients restarted treatment without a loss of major molecular response.

Dr Richter noted that the study is still ongoing, but, thus far, more than 80% of patients who restarted TKI therapy have achieved MR4 again.

The molecular relapse-free survival was 62% at 6 months after TKI stop, 56% at 12 months, 52% at 24 months, and 49% at 36 months.

There were 9 on-trial deaths, none of which were related to CML. Five patients died while in remission.

Previous studies revealed a TKI withdrawal syndrome that consists of (mostly transient) musculoskeletal pain or discomfort. In this study, 30.9% of patients (n=235) reported musculoskeletal symptoms, 226 with grade 1-2 events and 9 with grade 3 events.

Prognostic factors

The researchers performed prognostic modeling in 448 patients who previously received imatinib. Univariate analysis revealed no significant association between molecular relapse-free survival at 6 months and age, gender, depth of molecular response, Sokal score, EURO score, EUTOS score, or ELTS score.

However, TKI treatment duration and MR4 duration were both significantly (P<0.001) associated with major molecular response status at 6 months.

The odds ratio for treatment duration was 1.16 (95% CI, 1.08-1.25), which means that an additional year of imatinib treatment increases a patient’s odds of staying in major molecular response at 6 months by 16%.

The odds ratio for MR4 duration was also 1.16 (95% CI, 1.076-1.253), which means that an additional year in MR4 before TKI stop increases a patient’s odds of staying in major molecular response at 6 months by 16%.

Dr Richter noted that treatment duration and MR4 duration were highly correlated, which prevented a significant multiple model including both variables. He said the researchers will conduct further analyses to overcome the correlation between the 2 variables and determine an optimal cutoff for MR4 duration.

The team also plans to collect more data on pretreatment with interferon, as there is reason to suspect it has an influence on major molecular response duration after TKI discontinuation.

*Data in the abstract differ from data presented at the meeting.

Johan Richter, MD, PhD

COPENHAGEN—Results of a large study suggest that stopping treatment with tyrosine kinase inhibitors (TKIs) can be safe for patients with chronic myeloid leukemia (CML) in deep molecular response (MR4).

Six months after patients stopped receiving a TKI, the relapse-free survival was 62%. At 12 months, it was 56%.

Havinga longer duration of TKI treatment and a longer duration of deep molecular response were both associated with a higher likelihood of relapse-free survival.

These results, from the EURO-SKI trial, were presented at the 21st Congress of the European Hematology Association (abstract S145*) by Johan Richter, MD, PhD, of Skåne University Hospital in Lund, Sweden.

The goal of the EURO-SKI study was to define prognostic markers to increase the proportion of patients in durable deep molecular response after stopping TKI treatment.

The trial included 760 adults with chronic phase CML who were on TKI treatment for at least 3 years. Patients were either on their first TKI or on their second TKI due to toxicity with their first. (None had failed TKI treatment.)

Patients had been in MR4 (BCR/ABL <0.01%) for at least a year, which was confirmed by 3 consecutive polymerase chain reaction (PCR) results during the last 12 months. The final MR4 confirmation was performed in a EUTOS standardized laboratory.

After the final MR4 confirmation, patients stopped TKI treatment. They underwent real-time quantitative PCR (RQ-PCR) every 4 weeks for the first 6 months and every 6 weeks for the next 6 months. In years 2 and 3, they underwent RQ-PCR every third month.

The patients had a median age at diagnosis of 52 (range, 11.2-85.5) and a median age at TKI stop of 60.3 (range, 19.5-89.9). The median duration of TKI therapy was 7.6 years (range, 3.0-14.2), and the median duration of MR4 before TKI stop was 4.7 years (range, 1.0-13.3).

Most patients had received imatinib (n=710) as first-line TKI treatment, though some received nilotinib (n=35) or dasatinib (n=14). The type of first-line TKI was unknown in 1 patient. Second-line TKI treatment included imatinib (n=7), nilotinib (n=47), and dasatinib (n=57).

Relapse, survival, and safety

Six months after stopping TKI treatment, the cumulative incidence of molecular relapse was 37%. It was 43% at 12 months, 47% at 24 months, and 50% at 36 months.

In all, 347 patients had a molecular relapse. Seventy-two patients had BCR/ABL >1%, and 11 lost their complete cytogenetic response. None of the patients progressed to accelerated phase or blast crisis.

Among patients who restarted TKI treatment, the median time to restart was 4.1 months. Fourteen patients restarted treatment without a loss of major molecular response.

Dr Richter noted that the study is still ongoing, but, thus far, more than 80% of patients who restarted TKI therapy have achieved MR4 again.

The molecular relapse-free survival was 62% at 6 months after TKI stop, 56% at 12 months, 52% at 24 months, and 49% at 36 months.

There were 9 on-trial deaths, none of which were related to CML. Five patients died while in remission.

Previous studies revealed a TKI withdrawal syndrome that consists of (mostly transient) musculoskeletal pain or discomfort. In this study, 30.9% of patients (n=235) reported musculoskeletal symptoms, 226 with grade 1-2 events and 9 with grade 3 events.

Prognostic factors

The researchers performed prognostic modeling in 448 patients who previously received imatinib. Univariate analysis revealed no significant association between molecular relapse-free survival at 6 months and age, gender, depth of molecular response, Sokal score, EURO score, EUTOS score, or ELTS score.

However, TKI treatment duration and MR4 duration were both significantly (P<0.001) associated with major molecular response status at 6 months.

The odds ratio for treatment duration was 1.16 (95% CI, 1.08-1.25), which means that an additional year of imatinib treatment increases a patient’s odds of staying in major molecular response at 6 months by 16%.

The odds ratio for MR4 duration was also 1.16 (95% CI, 1.076-1.253), which means that an additional year in MR4 before TKI stop increases a patient’s odds of staying in major molecular response at 6 months by 16%.

Dr Richter noted that treatment duration and MR4 duration were highly correlated, which prevented a significant multiple model including both variables. He said the researchers will conduct further analyses to overcome the correlation between the 2 variables and determine an optimal cutoff for MR4 duration.

The team also plans to collect more data on pretreatment with interferon, as there is reason to suspect it has an influence on major molecular response duration after TKI discontinuation.

*Data in the abstract differ from data presented at the meeting.

Johan Richter, MD, PhD

COPENHAGEN—Results of a large study suggest that stopping treatment with tyrosine kinase inhibitors (TKIs) can be safe for patients with chronic myeloid leukemia (CML) in deep molecular response (MR4).

Six months after patients stopped receiving a TKI, the relapse-free survival was 62%. At 12 months, it was 56%.

Havinga longer duration of TKI treatment and a longer duration of deep molecular response were both associated with a higher likelihood of relapse-free survival.

These results, from the EURO-SKI trial, were presented at the 21st Congress of the European Hematology Association (abstract S145*) by Johan Richter, MD, PhD, of Skåne University Hospital in Lund, Sweden.

The goal of the EURO-SKI study was to define prognostic markers to increase the proportion of patients in durable deep molecular response after stopping TKI treatment.

The trial included 760 adults with chronic phase CML who were on TKI treatment for at least 3 years. Patients were either on their first TKI or on their second TKI due to toxicity with their first. (None had failed TKI treatment.)

Patients had been in MR4 (BCR/ABL <0.01%) for at least a year, which was confirmed by 3 consecutive polymerase chain reaction (PCR) results during the last 12 months. The final MR4 confirmation was performed in a EUTOS standardized laboratory.

After the final MR4 confirmation, patients stopped TKI treatment. They underwent real-time quantitative PCR (RQ-PCR) every 4 weeks for the first 6 months and every 6 weeks for the next 6 months. In years 2 and 3, they underwent RQ-PCR every third month.

The patients had a median age at diagnosis of 52 (range, 11.2-85.5) and a median age at TKI stop of 60.3 (range, 19.5-89.9). The median duration of TKI therapy was 7.6 years (range, 3.0-14.2), and the median duration of MR4 before TKI stop was 4.7 years (range, 1.0-13.3).

Most patients had received imatinib (n=710) as first-line TKI treatment, though some received nilotinib (n=35) or dasatinib (n=14). The type of first-line TKI was unknown in 1 patient. Second-line TKI treatment included imatinib (n=7), nilotinib (n=47), and dasatinib (n=57).

Relapse, survival, and safety

Six months after stopping TKI treatment, the cumulative incidence of molecular relapse was 37%. It was 43% at 12 months, 47% at 24 months, and 50% at 36 months.

In all, 347 patients had a molecular relapse. Seventy-two patients had BCR/ABL >1%, and 11 lost their complete cytogenetic response. None of the patients progressed to accelerated phase or blast crisis.

Among patients who restarted TKI treatment, the median time to restart was 4.1 months. Fourteen patients restarted treatment without a loss of major molecular response.

Dr Richter noted that the study is still ongoing, but, thus far, more than 80% of patients who restarted TKI therapy have achieved MR4 again.

The molecular relapse-free survival was 62% at 6 months after TKI stop, 56% at 12 months, 52% at 24 months, and 49% at 36 months.

There were 9 on-trial deaths, none of which were related to CML. Five patients died while in remission.

Previous studies revealed a TKI withdrawal syndrome that consists of (mostly transient) musculoskeletal pain or discomfort. In this study, 30.9% of patients (n=235) reported musculoskeletal symptoms, 226 with grade 1-2 events and 9 with grade 3 events.

Prognostic factors

The researchers performed prognostic modeling in 448 patients who previously received imatinib. Univariate analysis revealed no significant association between molecular relapse-free survival at 6 months and age, gender, depth of molecular response, Sokal score, EURO score, EUTOS score, or ELTS score.

However, TKI treatment duration and MR4 duration were both significantly (P<0.001) associated with major molecular response status at 6 months.

The odds ratio for treatment duration was 1.16 (95% CI, 1.08-1.25), which means that an additional year of imatinib treatment increases a patient’s odds of staying in major molecular response at 6 months by 16%.

The odds ratio for MR4 duration was also 1.16 (95% CI, 1.076-1.253), which means that an additional year in MR4 before TKI stop increases a patient’s odds of staying in major molecular response at 6 months by 16%.

Dr Richter noted that treatment duration and MR4 duration were highly correlated, which prevented a significant multiple model including both variables. He said the researchers will conduct further analyses to overcome the correlation between the 2 variables and determine an optimal cutoff for MR4 duration.

The team also plans to collect more data on pretreatment with interferon, as there is reason to suspect it has an influence on major molecular response duration after TKI discontinuation.

*Data in the abstract differ from data presented at the meeting.

Laura Franco, MD

COPENHAGEN—Results of a new study suggest that vitamin K antagonists (VKAs) and non-VKA oral anticoagulants (NOACs) can both confer an increased risk of major bleeding, but the type of bleeding tends to differ with the type of anticoagulant.

The research showed that patients taking VKAs were more likely to be hospitalized for intracranial hemorrhage (ICH), while patients taking NOACs were more likely to be hospitalized for gastrointestinal (GI) bleeding.

In addition, the 30-day mortality rate was significantly lower in patients who were taking NOACs than in those who were taking VKAs. However, there was no significant difference between the 2 treatment groups when the researchers assessed mortality according to the type of major bleeding.

Laura Franco, MD, of the University of Perugia in Italy, presented these findings at the 21st Congress of the European Hematology Association (abstract S139*).

For this study, Dr Franco and her colleagues wanted to evaluate the real-life clinical presentation, management, and outcome of major bleeding in patients on anticoagulants.

So the team analyzed a cohort of patients treated at 9 Italian hospitals and a group of patients enrolled in Germany’s Dresden NOAC registry.

Between September 2013 and May 2016, there were 874 patients who were hospitalized for major bleeding—220 of whom who were taking NOACs and 654 of whom were taking VKAs.

Overall, 44% (n=386) of patients were hospitalized for an ICH, and 30% (n=261) were hospitalized for GI bleeding.

The incidence of ICH was 22% (n=48) among patients who received NOACs and 52% (n=338) among patients who received VKAs. The odds ratio was 0.26 (95% CI, 0.18-0.37; P<0.001).

The incidence of GI major bleeding was 46% (n=102) in the NOAC group and 24% (n=159) in the VKA group. The odds ratio was 2.69 (95% CI, 1.95-3.70; P<0.001).

The incidence of 30-day mortality was significantly higher in the VKA group than the NOAC group—17% and 10%, respectively. The adjusted hazard ratio (aHR) was 0.59 (95% CI, 0.36-0.94, P=0.012).

However, when the researchers looked at 30-day mortality according to the site of major bleeding, they observed no significant differences between the NOAC and VKA groups.

The incidence of 30-day mortality among patients with ICH was 25% in both the NOAC and VKA groups (aHR=1.07; 95% CI, 0.57-1.97). And the incidence of 30-day mortality among patients with GI bleeding was 7% in the NOAC group and 10% in the VKA group (aHR=0.66; 95% CI, 0.26-1.68).

*Data in the abstract differ from data presented at the meeting.

Laura Franco, MD

COPENHAGEN—Results of a new study suggest that vitamin K antagonists (VKAs) and non-VKA oral anticoagulants (NOACs) can both confer an increased risk of major bleeding, but the type of bleeding tends to differ with the type of anticoagulant.

The research showed that patients taking VKAs were more likely to be hospitalized for intracranial hemorrhage (ICH), while patients taking NOACs were more likely to be hospitalized for gastrointestinal (GI) bleeding.

In addition, the 30-day mortality rate was significantly lower in patients who were taking NOACs than in those who were taking VKAs. However, there was no significant difference between the 2 treatment groups when the researchers assessed mortality according to the type of major bleeding.

Laura Franco, MD, of the University of Perugia in Italy, presented these findings at the 21st Congress of the European Hematology Association (abstract S139*).

For this study, Dr Franco and her colleagues wanted to evaluate the real-life clinical presentation, management, and outcome of major bleeding in patients on anticoagulants.

So the team analyzed a cohort of patients treated at 9 Italian hospitals and a group of patients enrolled in Germany’s Dresden NOAC registry.

Between September 2013 and May 2016, there were 874 patients who were hospitalized for major bleeding—220 of whom who were taking NOACs and 654 of whom were taking VKAs.

Overall, 44% (n=386) of patients were hospitalized for an ICH, and 30% (n=261) were hospitalized for GI bleeding.

The incidence of ICH was 22% (n=48) among patients who received NOACs and 52% (n=338) among patients who received VKAs. The odds ratio was 0.26 (95% CI, 0.18-0.37; P<0.001).

The incidence of GI major bleeding was 46% (n=102) in the NOAC group and 24% (n=159) in the VKA group. The odds ratio was 2.69 (95% CI, 1.95-3.70; P<0.001).

The incidence of 30-day mortality was significantly higher in the VKA group than the NOAC group—17% and 10%, respectively. The adjusted hazard ratio (aHR) was 0.59 (95% CI, 0.36-0.94, P=0.012).

However, when the researchers looked at 30-day mortality according to the site of major bleeding, they observed no significant differences between the NOAC and VKA groups.

The incidence of 30-day mortality among patients with ICH was 25% in both the NOAC and VKA groups (aHR=1.07; 95% CI, 0.57-1.97). And the incidence of 30-day mortality among patients with GI bleeding was 7% in the NOAC group and 10% in the VKA group (aHR=0.66; 95% CI, 0.26-1.68).

*Data in the abstract differ from data presented at the meeting.

Laura Franco, MD

COPENHAGEN—Results of a new study suggest that vitamin K antagonists (VKAs) and non-VKA oral anticoagulants (NOACs) can both confer an increased risk of major bleeding, but the type of bleeding tends to differ with the type of anticoagulant.

The research showed that patients taking VKAs were more likely to be hospitalized for intracranial hemorrhage (ICH), while patients taking NOACs were more likely to be hospitalized for gastrointestinal (GI) bleeding.

In addition, the 30-day mortality rate was significantly lower in patients who were taking NOACs than in those who were taking VKAs. However, there was no significant difference between the 2 treatment groups when the researchers assessed mortality according to the type of major bleeding.

Laura Franco, MD, of the University of Perugia in Italy, presented these findings at the 21st Congress of the European Hematology Association (abstract S139*).

For this study, Dr Franco and her colleagues wanted to evaluate the real-life clinical presentation, management, and outcome of major bleeding in patients on anticoagulants.

So the team analyzed a cohort of patients treated at 9 Italian hospitals and a group of patients enrolled in Germany’s Dresden NOAC registry.

Between September 2013 and May 2016, there were 874 patients who were hospitalized for major bleeding—220 of whom who were taking NOACs and 654 of whom were taking VKAs.

Overall, 44% (n=386) of patients were hospitalized for an ICH, and 30% (n=261) were hospitalized for GI bleeding.

The incidence of ICH was 22% (n=48) among patients who received NOACs and 52% (n=338) among patients who received VKAs. The odds ratio was 0.26 (95% CI, 0.18-0.37; P<0.001).

The incidence of GI major bleeding was 46% (n=102) in the NOAC group and 24% (n=159) in the VKA group. The odds ratio was 2.69 (95% CI, 1.95-3.70; P<0.001).

The incidence of 30-day mortality was significantly higher in the VKA group than the NOAC group—17% and 10%, respectively. The adjusted hazard ratio (aHR) was 0.59 (95% CI, 0.36-0.94, P=0.012).

However, when the researchers looked at 30-day mortality according to the site of major bleeding, they observed no significant differences between the NOAC and VKA groups.

The incidence of 30-day mortality among patients with ICH was 25% in both the NOAC and VKA groups (aHR=1.07; 95% CI, 0.57-1.97). And the incidence of 30-day mortality among patients with GI bleeding was 7% in the NOAC group and 10% in the VKA group (aHR=0.66; 95% CI, 0.26-1.68).

*Data in the abstract differ from data presented at the meeting.

Attendees at the 21st

Congress of the European

Hematology Association

COPENHAGEN—Results of the phase 3 PATCH trial suggest that platelet transfusions are not beneficial and can actually cause harm in patients with intracerebral hemorrhage (ICH) associated with antiplatelet therapy.

The study showed that the odds of death or dependence at 3 months were significantly higher among patients who received a platelet transfusion plus standard care than among patients who received standard care alone.

Patients who received a platelet transfusion also had a higher incidence of severe adverse events (SAEs) during hospital admission.

“PATCH shows that platelet transfusion seems harmful for patients with antiplatelet-associated ICH,” said study investigator Maria Koopman, PhD, of Sanquin Bloodbank in Amsterdam, The Netherlands.

“Pending further evidence, we think that platelet transfusions should not be used in this patient group.”

Dr Koopman presented results of the PATCH trial at the 21st Congress of the European Hematology Association (abstract LB2234). The study was also recently published in The Lancet.

Dr Koopman noted that, worldwide, there are 2 million cases of ICH each year, and more than 25% of these patients are taking antiplatelet therapy at ICH onset.

She and her colleagues theorized that because antiplatelet therapy can lead to hematoma growth and poor outcomes, platelet transfusions might modify the effect of antiplatelet therapy and improve patient outcomes.

To test this theory, the team studied ICH patients treated at 60 hospitals in The Netherlands, Scotland, and France.

Patients and treatment

The study included patients with spontaneous supratentorial ICH who were 18 years of age or older, had been using antiplatelet therapy for at least 7 days preceding ICH, and had a Glasgow Coma Scale score of 8 or higher.

The patients were randomized 1:1 to receive either standard care alone or standard care plus a platelet transfusion within 6 hours of the start of symptoms and within 90 minutes of diagnostic brain imaging.

In all, 190 patients were randomized—97 to the transfusion arm and 93 to the standard care arm. Ultimately, 93 patients actually received a platelet transfusion, and 91 received standard care alone.

Patient characteristics were generally balanced between the treatment arms. The mean age was 74.2 in the transfusion arm and 73.5 in the standard care arm. Median scores on the Glasgow Coma Scale were 14 (range, 13-15) and 15 (range, 13-15), respectively.

Comorbidities included cerebral infarction (38.4% and 40%, respectively), hypertension (72.3% and 72.8%, respectively), diabetes (15.5% and 18.9%, respectively), myocardial infarction (23.6% and 24.4%, respectively), and peripheral artery disease (16.5% and 4.4%, respectively).

Antiplatelet therapy consisted of a cyclooxygenase (COX) inhibitor (73.2% and 83.9%, respectively), a COX inhibitor plus dipyridamole (18.6% and 14%, respectively), an adenosine diphosphate (ADP) receptor inhibitor (4.1% and 1.1%, respectively), and an ADP inhibitor plus a COX inhibitor (3.1% and 1.1%, respectively).

Efficacy

The study’s primary outcome was a shift toward death or dependence, rated on the modified Rankin Scale (mRS), at 3 months after ICH, adjusted for hospital, antiplatelet therapy, and ICH score. The primary analysis was done in the intention-to-treat population (n=97 in the transfusion arm and 93 in the standard care arm).

The investigators found the odds of death or dependence at 3 months were higher in the platelet transfusion arm than the standard care arm. The adjusted common odds ratio (OR) was 2.05 (95% CI 1.18-3.56; P=0.0114).

The study’s secondary endpoints were survival at 3 months, poor outcome (dichotomous mRS 4-6 or 3-6) at 3 months, and hematoma growth on imaging within 24 hours.

The survival rate was lower in the transfusion arm than the standard care arm, although the difference was not statistically significant—68% and 77.4%, respectively (OR=0.62; 95% CI, 0.33-1.19; P=0.15).

Poor outcome was more likely in the transfusion arm than the standard care arm, with 72.2% and 55.9% of patients, respectively, having an mRS score of 4-6 (OR=2.04; 95% CI, 1.12-3.74; P=0.0195) and 88.7% and 81.7%, respectively, having an mRS score of 3-6 (OR=1.75; 95% CI, 0.77-3.97; P=0.18).

And there was no significant difference between the arms when it came to hematoma growth, with a median of 2.01 mL (interquartile range, 0.32-9.34) in the transfusion arm and 1.16 mL (interquartile range, 0.03-4.42) in the standard care arm (P=0.81).

Safety

Safety endpoints included thromboembolic events, transfusion reactions, and SAEs during hospital admission. The safety analysis was done in the intention-to-treat population (n=97 in the transfusion arm and 93 in the standard care arm) and the as-treated population (n=93 and 91, respectively).

In the as-treated population, the incidence of SAEs was 42% in the transfusion arm and 29% in the standard care arm (OR=1.74; 95% CI, 0.96-3.17). The incidence of any fatal SAE was 24% and 17%, respectively (OR=1.58; 95% CI, 1.77-3.22).

The incidence of SAEs due to ICH was 25% and 14%, respectively (OR=2.13; 95% CI, 1.01-4.50). The incidence of SAEs due to thromboembolism was 4% and 1%, respectively (OR=4.13; 95% CI, 0.45-37.67). And there was 1 SAE due to transfusion (OR=3.03; 95% CI, 0.12-75.37).

Attendees at the 21st

Congress of the European

Hematology Association

COPENHAGEN—Results of the phase 3 PATCH trial suggest that platelet transfusions are not beneficial and can actually cause harm in patients with intracerebral hemorrhage (ICH) associated with antiplatelet therapy.

The study showed that the odds of death or dependence at 3 months were significantly higher among patients who received a platelet transfusion plus standard care than among patients who received standard care alone.

Patients who received a platelet transfusion also had a higher incidence of severe adverse events (SAEs) during hospital admission.

“PATCH shows that platelet transfusion seems harmful for patients with antiplatelet-associated ICH,” said study investigator Maria Koopman, PhD, of Sanquin Bloodbank in Amsterdam, The Netherlands.

“Pending further evidence, we think that platelet transfusions should not be used in this patient group.”

Dr Koopman presented results of the PATCH trial at the 21st Congress of the European Hematology Association (abstract LB2234). The study was also recently published in The Lancet.

Dr Koopman noted that, worldwide, there are 2 million cases of ICH each year, and more than 25% of these patients are taking antiplatelet therapy at ICH onset.

She and her colleagues theorized that because antiplatelet therapy can lead to hematoma growth and poor outcomes, platelet transfusions might modify the effect of antiplatelet therapy and improve patient outcomes.

To test this theory, the team studied ICH patients treated at 60 hospitals in The Netherlands, Scotland, and France.

Patients and treatment

The study included patients with spontaneous supratentorial ICH who were 18 years of age or older, had been using antiplatelet therapy for at least 7 days preceding ICH, and had a Glasgow Coma Scale score of 8 or higher.

The patients were randomized 1:1 to receive either standard care alone or standard care plus a platelet transfusion within 6 hours of the start of symptoms and within 90 minutes of diagnostic brain imaging.

In all, 190 patients were randomized—97 to the transfusion arm and 93 to the standard care arm. Ultimately, 93 patients actually received a platelet transfusion, and 91 received standard care alone.

Patient characteristics were generally balanced between the treatment arms. The mean age was 74.2 in the transfusion arm and 73.5 in the standard care arm. Median scores on the Glasgow Coma Scale were 14 (range, 13-15) and 15 (range, 13-15), respectively.

Comorbidities included cerebral infarction (38.4% and 40%, respectively), hypertension (72.3% and 72.8%, respectively), diabetes (15.5% and 18.9%, respectively), myocardial infarction (23.6% and 24.4%, respectively), and peripheral artery disease (16.5% and 4.4%, respectively).

Antiplatelet therapy consisted of a cyclooxygenase (COX) inhibitor (73.2% and 83.9%, respectively), a COX inhibitor plus dipyridamole (18.6% and 14%, respectively), an adenosine diphosphate (ADP) receptor inhibitor (4.1% and 1.1%, respectively), and an ADP inhibitor plus a COX inhibitor (3.1% and 1.1%, respectively).

Efficacy

The study’s primary outcome was a shift toward death or dependence, rated on the modified Rankin Scale (mRS), at 3 months after ICH, adjusted for hospital, antiplatelet therapy, and ICH score. The primary analysis was done in the intention-to-treat population (n=97 in the transfusion arm and 93 in the standard care arm).

The investigators found the odds of death or dependence at 3 months were higher in the platelet transfusion arm than the standard care arm. The adjusted common odds ratio (OR) was 2.05 (95% CI 1.18-3.56; P=0.0114).

The study’s secondary endpoints were survival at 3 months, poor outcome (dichotomous mRS 4-6 or 3-6) at 3 months, and hematoma growth on imaging within 24 hours.

The survival rate was lower in the transfusion arm than the standard care arm, although the difference was not statistically significant—68% and 77.4%, respectively (OR=0.62; 95% CI, 0.33-1.19; P=0.15).

Poor outcome was more likely in the transfusion arm than the standard care arm, with 72.2% and 55.9% of patients, respectively, having an mRS score of 4-6 (OR=2.04; 95% CI, 1.12-3.74; P=0.0195) and 88.7% and 81.7%, respectively, having an mRS score of 3-6 (OR=1.75; 95% CI, 0.77-3.97; P=0.18).

And there was no significant difference between the arms when it came to hematoma growth, with a median of 2.01 mL (interquartile range, 0.32-9.34) in the transfusion arm and 1.16 mL (interquartile range, 0.03-4.42) in the standard care arm (P=0.81).

Safety

Safety endpoints included thromboembolic events, transfusion reactions, and SAEs during hospital admission. The safety analysis was done in the intention-to-treat population (n=97 in the transfusion arm and 93 in the standard care arm) and the as-treated population (n=93 and 91, respectively).

In the as-treated population, the incidence of SAEs was 42% in the transfusion arm and 29% in the standard care arm (OR=1.74; 95% CI, 0.96-3.17). The incidence of any fatal SAE was 24% and 17%, respectively (OR=1.58; 95% CI, 1.77-3.22).

The incidence of SAEs due to ICH was 25% and 14%, respectively (OR=2.13; 95% CI, 1.01-4.50). The incidence of SAEs due to thromboembolism was 4% and 1%, respectively (OR=4.13; 95% CI, 0.45-37.67). And there was 1 SAE due to transfusion (OR=3.03; 95% CI, 0.12-75.37).

Attendees at the 21st

Congress of the European

Hematology Association

COPENHAGEN—Results of the phase 3 PATCH trial suggest that platelet transfusions are not beneficial and can actually cause harm in patients with intracerebral hemorrhage (ICH) associated with antiplatelet therapy.

The study showed that the odds of death or dependence at 3 months were significantly higher among patients who received a platelet transfusion plus standard care than among patients who received standard care alone.

Patients who received a platelet transfusion also had a higher incidence of severe adverse events (SAEs) during hospital admission.

“PATCH shows that platelet transfusion seems harmful for patients with antiplatelet-associated ICH,” said study investigator Maria Koopman, PhD, of Sanquin Bloodbank in Amsterdam, The Netherlands.

“Pending further evidence, we think that platelet transfusions should not be used in this patient group.”

Dr Koopman presented results of the PATCH trial at the 21st Congress of the European Hematology Association (abstract LB2234). The study was also recently published in The Lancet.

Dr Koopman noted that, worldwide, there are 2 million cases of ICH each year, and more than 25% of these patients are taking antiplatelet therapy at ICH onset.

She and her colleagues theorized that because antiplatelet therapy can lead to hematoma growth and poor outcomes, platelet transfusions might modify the effect of antiplatelet therapy and improve patient outcomes.

To test this theory, the team studied ICH patients treated at 60 hospitals in The Netherlands, Scotland, and France.

Patients and treatment

The study included patients with spontaneous supratentorial ICH who were 18 years of age or older, had been using antiplatelet therapy for at least 7 days preceding ICH, and had a Glasgow Coma Scale score of 8 or higher.

The patients were randomized 1:1 to receive either standard care alone or standard care plus a platelet transfusion within 6 hours of the start of symptoms and within 90 minutes of diagnostic brain imaging.

In all, 190 patients were randomized—97 to the transfusion arm and 93 to the standard care arm. Ultimately, 93 patients actually received a platelet transfusion, and 91 received standard care alone.

Patient characteristics were generally balanced between the treatment arms. The mean age was 74.2 in the transfusion arm and 73.5 in the standard care arm. Median scores on the Glasgow Coma Scale were 14 (range, 13-15) and 15 (range, 13-15), respectively.

Comorbidities included cerebral infarction (38.4% and 40%, respectively), hypertension (72.3% and 72.8%, respectively), diabetes (15.5% and 18.9%, respectively), myocardial infarction (23.6% and 24.4%, respectively), and peripheral artery disease (16.5% and 4.4%, respectively).

Antiplatelet therapy consisted of a cyclooxygenase (COX) inhibitor (73.2% and 83.9%, respectively), a COX inhibitor plus dipyridamole (18.6% and 14%, respectively), an adenosine diphosphate (ADP) receptor inhibitor (4.1% and 1.1%, respectively), and an ADP inhibitor plus a COX inhibitor (3.1% and 1.1%, respectively).

Efficacy

The study’s primary outcome was a shift toward death or dependence, rated on the modified Rankin Scale (mRS), at 3 months after ICH, adjusted for hospital, antiplatelet therapy, and ICH score. The primary analysis was done in the intention-to-treat population (n=97 in the transfusion arm and 93 in the standard care arm).

The investigators found the odds of death or dependence at 3 months were higher in the platelet transfusion arm than the standard care arm. The adjusted common odds ratio (OR) was 2.05 (95% CI 1.18-3.56; P=0.0114).

The study’s secondary endpoints were survival at 3 months, poor outcome (dichotomous mRS 4-6 or 3-6) at 3 months, and hematoma growth on imaging within 24 hours.

The survival rate was lower in the transfusion arm than the standard care arm, although the difference was not statistically significant—68% and 77.4%, respectively (OR=0.62; 95% CI, 0.33-1.19; P=0.15).

Poor outcome was more likely in the transfusion arm than the standard care arm, with 72.2% and 55.9% of patients, respectively, having an mRS score of 4-6 (OR=2.04; 95% CI, 1.12-3.74; P=0.0195) and 88.7% and 81.7%, respectively, having an mRS score of 3-6 (OR=1.75; 95% CI, 0.77-3.97; P=0.18).

And there was no significant difference between the arms when it came to hematoma growth, with a median of 2.01 mL (interquartile range, 0.32-9.34) in the transfusion arm and 1.16 mL (interquartile range, 0.03-4.42) in the standard care arm (P=0.81).

Safety

Safety endpoints included thromboembolic events, transfusion reactions, and SAEs during hospital admission. The safety analysis was done in the intention-to-treat population (n=97 in the transfusion arm and 93 in the standard care arm) and the as-treated population (n=93 and 91, respectively).

In the as-treated population, the incidence of SAEs was 42% in the transfusion arm and 29% in the standard care arm (OR=1.74; 95% CI, 0.96-3.17). The incidence of any fatal SAE was 24% and 17%, respectively (OR=1.58; 95% CI, 1.77-3.22).

The incidence of SAEs due to ICH was 25% and 14%, respectively (OR=2.13; 95% CI, 1.01-4.50). The incidence of SAEs due to thromboembolism was 4% and 1%, respectively (OR=4.13; 95% CI, 0.45-37.67). And there was 1 SAE due to transfusion (OR=3.03; 95% CI, 0.12-75.37).

Anas Younes, MD

COPENHAGEN—The PD-1 checkpoint inhibitor nivolumab can address an unmet need in patients with classical Hodgkin lymphoma (cHL) who have progressive or relapsed disease, according to a speaker at the 21st Congress of the European Hematology Association.

In the phase 2 Checkmate-205 trial, nivolumab produced an objective response rate of 66% in cHL patients who had relapsed or progressed after autologous hematopoietic stem cell transplant (HSCT) and subsequent brentuximab vedotin.

The median duration of response was 7.8 months, and most patients had a response that was ongoing at the time of analysis.

Although the safety profile of nivolumab was considered “acceptable” by researchers, the drug has been linked to serious complications, including death, among patients who proceeded to allogeneic HSCT after receiving nivolumab.

Still, nivolumab is “an important new therapy to meet the unmet need” in cHL, according to Anas Younes, MD, of Memorial Sloan Kettering Cancer Center in New York, New York.

Dr Younes presented results with nivolumab from cohort B of the Checkmate-205 trial as abstract S793. Checkmate-205 was sponsored by Bristol-Myers Squibb.

Cohort B included 80 cHL patients who had relapsed or progressed after autologous HSCT and post-transplant brentuximab vedotin. (Cohort A included patients who had not previously received brentuximab vedotin.)

The patients’ median age was 37 (range, 18-72), and 64% were male. The median number of prior lines of therapy was 4 (range, 3-15), and 49% of patients had received at least 5 previous lines of therapy.

Seventy-four percent of patients had previously received radiation, 93% had received 1 prior autologous HSCT, and 8% had received 2. All patients had received brentuximab vedotin after transplant, and 54% had not responded to that treatment.

Study treatment

Patients received nivolumab at 3 mg/kg intravenously every 2 weeks until disease progression or unacceptable toxicity.

At a median follow-up of 8.9 months (range, 1.9-11.7), 36% of patients had come off treatment—16% due to disease progression, 5% due to toxicity, 8% because they had gone on to allogeneic HSCT, and 8% for other reasons (the patient’s request, the investigator’s decision, the patient was lost to follow-up, or the reason was not reported).

Dr Younes noted that all patients who stopped nivolumab to undergo HSCT were still alive at the data cut-off.

Efficacy

The objective response rate, per an independent radiologic review committee, was 66%. Nine percent of patients achieved a complete response, 58% had a partial response, 23% had stable disease, and 8% had progressive disease. The committee was unable to determine the status of 4% of patients.

The median time to response was 2.1 months, and the estimated median duration of response was 7.8 months.

“Keep in mind that the majority of patients are still on therapy, so this is expected to improve with time,” Dr Younes said.

The majority of responses (62%) were ongoing at the time of analysis. In an exploratory analysis, the researchers observed that 72% of patients who did not respond to their most recent prior brentuximab vedotin treatment did respond to nivolumab.

At 6 months, the progression-free survival rate was 77%, and the overall survival rate was 99%. The median progression-free survival was 10 months, and the median overall survival has not been reached.

Dr Younes said that, although the follow-up is short, the survival data are “still impressive.”

Safety

Adverse events (AEs) occurred in 99% of patients, grade 3/4 AEs occurred in 40% of patients, and there was 1 grade 5 AE (multi-organ failure due to Epstein-Barr-virus-positive T-cell lymphoma).

Treatment-related AEs occurred in 90% of patients. The most common of these were fatigue (25%), infusion-related reactions (20%), rash (16%), arthralgia (14%), pyrexia (14%), nausea (13%), diarrhea (10%), and pruritus (10%).

Treatment-related serious AEs occurred in 6% of patients and included pyrexia, tumor progression, arrhythmia, infusion reactions, septic meningitis, and pneumonia.

Extended safety follow-up of cHL patients treated in the nivolumab clinical trial program who were subsequently treated with allogeneic HSCT (n=17) revealed complications, including fatal events.

A warning about such complications has been added to the US prescribing information for nivolumab, which was recently granted accelerated approval from the US Food and Drug Administration (FDA) to treat patients with relapsed or refractory cHL who have received an autologous HSCT and post-transplant brentuximab vedotin.

Because of these transplant-related deaths, the FDA has advised that healthcare professionals follow patients closely for early evidence of transplant-related complications, such as hyperacute graft-versus-host disease, severe acute graft-versus-host disease, steroid-requiring febrile syndrome, hepatic veno-occlusive disease, and other immune-mediated adverse reactions.

The FDA has also required that Bristol-Myers Squibb further study the safety of allogeneic HSCT after nivolumab.

Anas Younes, MD

COPENHAGEN—The PD-1 checkpoint inhibitor nivolumab can address an unmet need in patients with classical Hodgkin lymphoma (cHL) who have progressive or relapsed disease, according to a speaker at the 21st Congress of the European Hematology Association.

In the phase 2 Checkmate-205 trial, nivolumab produced an objective response rate of 66% in cHL patients who had relapsed or progressed after autologous hematopoietic stem cell transplant (HSCT) and subsequent brentuximab vedotin.

The median duration of response was 7.8 months, and most patients had a response that was ongoing at the time of analysis.

Although the safety profile of nivolumab was considered “acceptable” by researchers, the drug has been linked to serious complications, including death, among patients who proceeded to allogeneic HSCT after receiving nivolumab.

Still, nivolumab is “an important new therapy to meet the unmet need” in cHL, according to Anas Younes, MD, of Memorial Sloan Kettering Cancer Center in New York, New York.

Dr Younes presented results with nivolumab from cohort B of the Checkmate-205 trial as abstract S793. Checkmate-205 was sponsored by Bristol-Myers Squibb.

Cohort B included 80 cHL patients who had relapsed or progressed after autologous HSCT and post-transplant brentuximab vedotin. (Cohort A included patients who had not previously received brentuximab vedotin.)

The patients’ median age was 37 (range, 18-72), and 64% were male. The median number of prior lines of therapy was 4 (range, 3-15), and 49% of patients had received at least 5 previous lines of therapy.

Seventy-four percent of patients had previously received radiation, 93% had received 1 prior autologous HSCT, and 8% had received 2. All patients had received brentuximab vedotin after transplant, and 54% had not responded to that treatment.

Study treatment

Patients received nivolumab at 3 mg/kg intravenously every 2 weeks until disease progression or unacceptable toxicity.

At a median follow-up of 8.9 months (range, 1.9-11.7), 36% of patients had come off treatment—16% due to disease progression, 5% due to toxicity, 8% because they had gone on to allogeneic HSCT, and 8% for other reasons (the patient’s request, the investigator’s decision, the patient was lost to follow-up, or the reason was not reported).

Dr Younes noted that all patients who stopped nivolumab to undergo HSCT were still alive at the data cut-off.

Efficacy

The objective response rate, per an independent radiologic review committee, was 66%. Nine percent of patients achieved a complete response, 58% had a partial response, 23% had stable disease, and 8% had progressive disease. The committee was unable to determine the status of 4% of patients.

The median time to response was 2.1 months, and the estimated median duration of response was 7.8 months.

“Keep in mind that the majority of patients are still on therapy, so this is expected to improve with time,” Dr Younes said.

The majority of responses (62%) were ongoing at the time of analysis. In an exploratory analysis, the researchers observed that 72% of patients who did not respond to their most recent prior brentuximab vedotin treatment did respond to nivolumab.

At 6 months, the progression-free survival rate was 77%, and the overall survival rate was 99%. The median progression-free survival was 10 months, and the median overall survival has not been reached.

Dr Younes said that, although the follow-up is short, the survival data are “still impressive.”

Safety

Adverse events (AEs) occurred in 99% of patients, grade 3/4 AEs occurred in 40% of patients, and there was 1 grade 5 AE (multi-organ failure due to Epstein-Barr-virus-positive T-cell lymphoma).

Treatment-related AEs occurred in 90% of patients. The most common of these were fatigue (25%), infusion-related reactions (20%), rash (16%), arthralgia (14%), pyrexia (14%), nausea (13%), diarrhea (10%), and pruritus (10%).

Treatment-related serious AEs occurred in 6% of patients and included pyrexia, tumor progression, arrhythmia, infusion reactions, septic meningitis, and pneumonia.

Extended safety follow-up of cHL patients treated in the nivolumab clinical trial program who were subsequently treated with allogeneic HSCT (n=17) revealed complications, including fatal events.

A warning about such complications has been added to the US prescribing information for nivolumab, which was recently granted accelerated approval from the US Food and Drug Administration (FDA) to treat patients with relapsed or refractory cHL who have received an autologous HSCT and post-transplant brentuximab vedotin.

Because of these transplant-related deaths, the FDA has advised that healthcare professionals follow patients closely for early evidence of transplant-related complications, such as hyperacute graft-versus-host disease, severe acute graft-versus-host disease, steroid-requiring febrile syndrome, hepatic veno-occlusive disease, and other immune-mediated adverse reactions.

The FDA has also required that Bristol-Myers Squibb further study the safety of allogeneic HSCT after nivolumab.

Anas Younes, MD

COPENHAGEN—The PD-1 checkpoint inhibitor nivolumab can address an unmet need in patients with classical Hodgkin lymphoma (cHL) who have progressive or relapsed disease, according to a speaker at the 21st Congress of the European Hematology Association.

In the phase 2 Checkmate-205 trial, nivolumab produced an objective response rate of 66% in cHL patients who had relapsed or progressed after autologous hematopoietic stem cell transplant (HSCT) and subsequent brentuximab vedotin.

The median duration of response was 7.8 months, and most patients had a response that was ongoing at the time of analysis.

Although the safety profile of nivolumab was considered “acceptable” by researchers, the drug has been linked to serious complications, including death, among patients who proceeded to allogeneic HSCT after receiving nivolumab.

Still, nivolumab is “an important new therapy to meet the unmet need” in cHL, according to Anas Younes, MD, of Memorial Sloan Kettering Cancer Center in New York, New York.

Dr Younes presented results with nivolumab from cohort B of the Checkmate-205 trial as abstract S793. Checkmate-205 was sponsored by Bristol-Myers Squibb.

Cohort B included 80 cHL patients who had relapsed or progressed after autologous HSCT and post-transplant brentuximab vedotin. (Cohort A included patients who had not previously received brentuximab vedotin.)

The patients’ median age was 37 (range, 18-72), and 64% were male. The median number of prior lines of therapy was 4 (range, 3-15), and 49% of patients had received at least 5 previous lines of therapy.

Seventy-four percent of patients had previously received radiation, 93% had received 1 prior autologous HSCT, and 8% had received 2. All patients had received brentuximab vedotin after transplant, and 54% had not responded to that treatment.

Study treatment

Patients received nivolumab at 3 mg/kg intravenously every 2 weeks until disease progression or unacceptable toxicity.

At a median follow-up of 8.9 months (range, 1.9-11.7), 36% of patients had come off treatment—16% due to disease progression, 5% due to toxicity, 8% because they had gone on to allogeneic HSCT, and 8% for other reasons (the patient’s request, the investigator’s decision, the patient was lost to follow-up, or the reason was not reported).

Dr Younes noted that all patients who stopped nivolumab to undergo HSCT were still alive at the data cut-off.

Efficacy

The objective response rate, per an independent radiologic review committee, was 66%. Nine percent of patients achieved a complete response, 58% had a partial response, 23% had stable disease, and 8% had progressive disease. The committee was unable to determine the status of 4% of patients.

The median time to response was 2.1 months, and the estimated median duration of response was 7.8 months.

“Keep in mind that the majority of patients are still on therapy, so this is expected to improve with time,” Dr Younes said.

The majority of responses (62%) were ongoing at the time of analysis. In an exploratory analysis, the researchers observed that 72% of patients who did not respond to their most recent prior brentuximab vedotin treatment did respond to nivolumab.

At 6 months, the progression-free survival rate was 77%, and the overall survival rate was 99%. The median progression-free survival was 10 months, and the median overall survival has not been reached.

Dr Younes said that, although the follow-up is short, the survival data are “still impressive.”

Safety

Adverse events (AEs) occurred in 99% of patients, grade 3/4 AEs occurred in 40% of patients, and there was 1 grade 5 AE (multi-organ failure due to Epstein-Barr-virus-positive T-cell lymphoma).

Treatment-related AEs occurred in 90% of patients. The most common of these were fatigue (25%), infusion-related reactions (20%), rash (16%), arthralgia (14%), pyrexia (14%), nausea (13%), diarrhea (10%), and pruritus (10%).

Treatment-related serious AEs occurred in 6% of patients and included pyrexia, tumor progression, arrhythmia, infusion reactions, septic meningitis, and pneumonia.

Extended safety follow-up of cHL patients treated in the nivolumab clinical trial program who were subsequently treated with allogeneic HSCT (n=17) revealed complications, including fatal events.

A warning about such complications has been added to the US prescribing information for nivolumab, which was recently granted accelerated approval from the US Food and Drug Administration (FDA) to treat patients with relapsed or refractory cHL who have received an autologous HSCT and post-transplant brentuximab vedotin.

Because of these transplant-related deaths, the FDA has advised that healthcare professionals follow patients closely for early evidence of transplant-related complications, such as hyperacute graft-versus-host disease, severe acute graft-versus-host disease, steroid-requiring febrile syndrome, hepatic veno-occlusive disease, and other immune-mediated adverse reactions.

The FDA has also required that Bristol-Myers Squibb further study the safety of allogeneic HSCT after nivolumab.

 

 

Max S. Topp, MD

 

COPENHAGEN—Interim results from the phase 3 TOWER trial suggest blinatumomab can prolong overall survival (OS) when compared to standard care in adults with Ph-negative, relapsed/refractory B-cell precursor acute lymphoblastic leukemia (B-ALL).

The median OS for patients treated with blinatumomab was nearly double the median OS of patients who received standard chemotherapy (investigator’s choice of 4 different regimens).

Based on these results, Amgen, the company sponsoring the trial, decided to stop it early.

“This was the first study to show that immunotherapy can outcompete chemotherapy,” said Max S. Topp, MD, of University Hospital of Wuerzburg in Germany.

Dr Topp presented results from this study at the 21st Congress of the European Hematology Association (abstract S149).

Patients and treatment

The TOWER trial enrolled and randomized 405 patients with Ph-negative, relapsed/refractory B-ALL, and 376 of them ultimately received treatment.

The patients received blinatumomab (n=267) or investigator’s choice of 1 of 4 protocol-defined standard chemotherapy regimens (n=109):

• FLAG (fludarabine, high-dose cytarabine, and granulocyte-colony stimulating factor), with or without an anthracycline (n=49, 45%)
• A high-dose cytarabine-based regimen (n=19, 17%)
• A high-dose methotrexate-based regimen (n=22, 20%)
• A clofarabine-based regimen (n=19, 17%).

Patients who received blinatumomab received it as a continuous infusion, 4 weeks on and 2 weeks off, at 9 µg/day for 7 days, then 28 µg/day on weeks 2-4. They received 2 cycles of induction, which was followed by 3 cycles of consolidation if they had ≤5% blasts.

If patients still had ≤5% blasts after consolidation, they received up to 12 months of blinatumomab maintenance. Maintenance was a continuous infusion, 4 weeks on and 8 weeks off, at 28 µg/day.

Patient characteristics were similar between the treatment arms. The median age was 37 in both arms (overall range, 18-80). About 40% of patients in the blinatumomab arm and 50% in the chemotherapy arm had not received any prior salvage regimens.

More than 30% of patients in both arms had undergone an allogeneic hematopoietic stem cell transplant (allo-HSCT), and about 20% were primary refractory. Roughly 30% of blinatumomab-treated patients were refractory to salvage therapy, as were more than 20% of chemotherapy-treated patients.

Response and survival

During induction, in the intent-to-treat population (n=271 in the blinatumomab arm and 134 in the chemotherapy arm), the overall response rate was 44% in the blinatumomab arm and 25% in the chemotherapy arm (P<0.001). The complete response rates were 34% and 16%, respectively.

Among patients who received their assigned treatment (n=267 in the blinatumomab arm and 109 in the chemotherapy arm), the overall response rates were 45% and 30%, respectively (P=0.007).

In the intent-to-treat population, the median OS was 7.7 months (95% CI, 5.6-9.6) in the blinatumomab arm and 4 months (95% CI, 2.9-5.3) in the chemotherapy arm (hazard ratio=0.71, P=0.012). The survival curves were similar in the as-treated population.

Dr Topp noted that the improvement in OS with blinatumomab was consistent across subgroups, regardless of age, prior salvage therapy, or prior allo-HSCT.

Dr Topp and his colleagues also considered the effect post-treatment allo-HSCT might have on OS. Sixty-five patients in the blinatumomab arm and 32 in the chemotherapy arm went on to receive an allo-HSCT (24% of patients in both arms).

When the researchers censored for post-treatment allo-HSCT, the median OS was 6.9 months in the blinatumomab arm and 3.9 months in the chemotherapy arm (hazard ratio=0.66, P=0.004).

Safety

In the as-treated population, 99% of patients in both arms experienced adverse events (AEs).


The incidence of grade 3 AEs was 37% in the blinatumomab arm and 30% in the chemotherapy arm. The incidence of grade 4 AEs was 31% and 44%, respectively. The incidence of grade 5 AEs was 19% and 17%, respectively.

Grade 3 or higher AEs of interest, according to Dr Topp, were infection (34% with blinatumomab and 52% with chemotherapy), neutropenia (38% and 58%, respectively), neurologic events (9% and 8%, respectively), and cytokine release syndrome (5% and 0%, respectively).

Seven patients—5 in the blinatumomab arm and 2 in the chemotherapy arm—who did not undergo allo-HSCT died during the study without documented relapse.

 

 

Max S. Topp, MD

 

COPENHAGEN—Interim results from the phase 3 TOWER trial suggest blinatumomab can prolong overall survival (OS) when compared to standard care in adults with Ph-negative, relapsed/refractory B-cell precursor acute lymphoblastic leukemia (B-ALL).

The median OS for patients treated with blinatumomab was nearly double the median OS of patients who received standard chemotherapy (investigator’s choice of 4 different regimens).

Based on these results, Amgen, the company sponsoring the trial, decided to stop it early.

“This was the first study to show that immunotherapy can outcompete chemotherapy,” said Max S. Topp, MD, of University Hospital of Wuerzburg in Germany.

Dr Topp presented results from this study at the 21st Congress of the European Hematology Association (abstract S149).

Patients and treatment

The TOWER trial enrolled and randomized 405 patients with Ph-negative, relapsed/refractory B-ALL, and 376 of them ultimately received treatment.

The patients received blinatumomab (n=267) or investigator’s choice of 1 of 4 protocol-defined standard chemotherapy regimens (n=109):

• FLAG (fludarabine, high-dose cytarabine, and granulocyte-colony stimulating factor), with or without an anthracycline (n=49, 45%)
• A high-dose cytarabine-based regimen (n=19, 17%)
• A high-dose methotrexate-based regimen (n=22, 20%)
• A clofarabine-based regimen (n=19, 17%).

Patients who received blinatumomab received it as a continuous infusion, 4 weeks on and 2 weeks off, at 9 µg/day for 7 days, then 28 µg/day on weeks 2-4. They received 2 cycles of induction, which was followed by 3 cycles of consolidation if they had ≤5% blasts.

If patients still had ≤5% blasts after consolidation, they received up to 12 months of blinatumomab maintenance. Maintenance was a continuous infusion, 4 weeks on and 8 weeks off, at 28 µg/day.

Patient characteristics were similar between the treatment arms. The median age was 37 in both arms (overall range, 18-80). About 40% of patients in the blinatumomab arm and 50% in the chemotherapy arm had not received any prior salvage regimens.

More than 30% of patients in both arms had undergone an allogeneic hematopoietic stem cell transplant (allo-HSCT), and about 20% were primary refractory. Roughly 30% of blinatumomab-treated patients were refractory to salvage therapy, as were more than 20% of chemotherapy-treated patients.

Response and survival

During induction, in the intent-to-treat population (n=271 in the blinatumomab arm and 134 in the chemotherapy arm), the overall response rate was 44% in the blinatumomab arm and 25% in the chemotherapy arm (P<0.001). The complete response rates were 34% and 16%, respectively.

Among patients who received their assigned treatment (n=267 in the blinatumomab arm and 109 in the chemotherapy arm), the overall response rates were 45% and 30%, respectively (P=0.007).

In the intent-to-treat population, the median OS was 7.7 months (95% CI, 5.6-9.6) in the blinatumomab arm and 4 months (95% CI, 2.9-5.3) in the chemotherapy arm (hazard ratio=0.71, P=0.012). The survival curves were similar in the as-treated population.

Dr Topp noted that the improvement in OS with blinatumomab was consistent across subgroups, regardless of age, prior salvage therapy, or prior allo-HSCT.

Dr Topp and his colleagues also considered the effect post-treatment allo-HSCT might have on OS. Sixty-five patients in the blinatumomab arm and 32 in the chemotherapy arm went on to receive an allo-HSCT (24% of patients in both arms).

When the researchers censored for post-treatment allo-HSCT, the median OS was 6.9 months in the blinatumomab arm and 3.9 months in the chemotherapy arm (hazard ratio=0.66, P=0.004).

Safety

In the as-treated population, 99% of patients in both arms experienced adverse events (AEs).


The incidence of grade 3 AEs was 37% in the blinatumomab arm and 30% in the chemotherapy arm. The incidence of grade 4 AEs was 31% and 44%, respectively. The incidence of grade 5 AEs was 19% and 17%, respectively.

Grade 3 or higher AEs of interest, according to Dr Topp, were infection (34% with blinatumomab and 52% with chemotherapy), neutropenia (38% and 58%, respectively), neurologic events (9% and 8%, respectively), and cytokine release syndrome (5% and 0%, respectively).

Seven patients—5 in the blinatumomab arm and 2 in the chemotherapy arm—who did not undergo allo-HSCT died during the study without documented relapse.

 

 

Max S. Topp, MD

 

COPENHAGEN—Interim results from the phase 3 TOWER trial suggest blinatumomab can prolong overall survival (OS) when compared to standard care in adults with Ph-negative, relapsed/refractory B-cell precursor acute lymphoblastic leukemia (B-ALL).

The median OS for patients treated with blinatumomab was nearly double the median OS of patients who received standard chemotherapy (investigator’s choice of 4 different regimens).

Based on these results, Amgen, the company sponsoring the trial, decided to stop it early.

“This was the first study to show that immunotherapy can outcompete chemotherapy,” said Max S. Topp, MD, of University Hospital of Wuerzburg in Germany.

Dr Topp presented results from this study at the 21st Congress of the European Hematology Association (abstract S149).

Patients and treatment

The TOWER trial enrolled and randomized 405 patients with Ph-negative, relapsed/refractory B-ALL, and 376 of them ultimately received treatment.

The patients received blinatumomab (n=267) or investigator’s choice of 1 of 4 protocol-defined standard chemotherapy regimens (n=109):

• FLAG (fludarabine, high-dose cytarabine, and granulocyte-colony stimulating factor), with or without an anthracycline (n=49, 45%)
• A high-dose cytarabine-based regimen (n=19, 17%)
• A high-dose methotrexate-based regimen (n=22, 20%)
• A clofarabine-based regimen (n=19, 17%).

Patients who received blinatumomab received it as a continuous infusion, 4 weeks on and 2 weeks off, at 9 µg/day for 7 days, then 28 µg/day on weeks 2-4. They received 2 cycles of induction, which was followed by 3 cycles of consolidation if they had ≤5% blasts.

If patients still had ≤5% blasts after consolidation, they received up to 12 months of blinatumomab maintenance. Maintenance was a continuous infusion, 4 weeks on and 8 weeks off, at 28 µg/day.

Patient characteristics were similar between the treatment arms. The median age was 37 in both arms (overall range, 18-80). About 40% of patients in the blinatumomab arm and 50% in the chemotherapy arm had not received any prior salvage regimens.

More than 30% of patients in both arms had undergone an allogeneic hematopoietic stem cell transplant (allo-HSCT), and about 20% were primary refractory. Roughly 30% of blinatumomab-treated patients were refractory to salvage therapy, as were more than 20% of chemotherapy-treated patients.

Response and survival

During induction, in the intent-to-treat population (n=271 in the blinatumomab arm and 134 in the chemotherapy arm), the overall response rate was 44% in the blinatumomab arm and 25% in the chemotherapy arm (P<0.001). The complete response rates were 34% and 16%, respectively.

Among patients who received their assigned treatment (n=267 in the blinatumomab arm and 109 in the chemotherapy arm), the overall response rates were 45% and 30%, respectively (P=0.007).

In the intent-to-treat population, the median OS was 7.7 months (95% CI, 5.6-9.6) in the blinatumomab arm and 4 months (95% CI, 2.9-5.3) in the chemotherapy arm (hazard ratio=0.71, P=0.012). The survival curves were similar in the as-treated population.

Dr Topp noted that the improvement in OS with blinatumomab was consistent across subgroups, regardless of age, prior salvage therapy, or prior allo-HSCT.

Dr Topp and his colleagues also considered the effect post-treatment allo-HSCT might have on OS. Sixty-five patients in the blinatumomab arm and 32 in the chemotherapy arm went on to receive an allo-HSCT (24% of patients in both arms).

When the researchers censored for post-treatment allo-HSCT, the median OS was 6.9 months in the blinatumomab arm and 3.9 months in the chemotherapy arm (hazard ratio=0.66, P=0.004).

Safety

In the as-treated population, 99% of patients in both arms experienced adverse events (AEs).


The incidence of grade 3 AEs was 37% in the blinatumomab arm and 30% in the chemotherapy arm. The incidence of grade 4 AEs was 31% and 44%, respectively. The incidence of grade 5 AEs was 19% and 17%, respectively.

Grade 3 or higher AEs of interest, according to Dr Topp, were infection (34% with blinatumomab and 52% with chemotherapy), neutropenia (38% and 58%, respectively), neurologic events (9% and 8%, respectively), and cytokine release syndrome (5% and 0%, respectively).

Seven patients—5 in the blinatumomab arm and 2 in the chemotherapy arm—who did not undergo allo-HSCT died during the study without documented relapse.

Uwe Platzbecker, MD

COPENHAGEN—The erythropoiesis-stimulating agent (ESA) darbepoetin alfa can provide a clinical benefit in patients with lower-risk myelodysplastic syndromes (MDS), a phase 3 trial suggests.

In the ARCADE trial, darbepoetin alfa significantly reduced the incidence of red blood cell (RBC) transfusions in patients with low- and intermediate-1 risk myelodysplastic syndrome (MDS), when compared to placebo.

The ESA also significantly improved erythroid response.

In addition, researchers said adverse events (AEs) were generally balanced between the darbepoetin alfa and placebo arms.

Uwe Platzbecker, MD, of University Hospital Carl Gustav Carus Dresden in Germany, presented these results at the 21st Congress of the European Hematology Association (abstract S128). The ARCADE trial was sponsored by Amgen.

Dr Platzbecker noted that, although ESAs are recommended in clinical guidelines to treat anemia in patients with lower-risk MDS, the drugs are not widely approved for this indication.

So, in the ARCADE trial, he and his colleagues assessed darbepoetin alfa in patients with low- or intermediate-1 risk MDS who had not previously taken ESAs or biologic response modifiers.

The patients had hemoglobin levels ≤10 g/dL, endogenous erythropoietin levels ≤500 mU/mL, and low transfusion burden (<4 RBC units in each of 2 consecutive 8-week periods prior to randomization).

During a 24-week period, 147 patients received either darbepoetin alfa at 500 μg (n=97) or placebo (n=49) every 3 weeks. The ESA dose was withheld if patients’ hemoglobin was >12.0 g/dL and decreased if hemoglobin increased by >1.5 g/dL in 3 weeks without transfusion.

At week 25, when the primary and key secondary endpoints were assessed, patients underwent an end-of-treatment period visit. They could then enter a 48-week active treatment period and cross over to receive darbepoetin alfa, with dose escalation allowed beginning on week 31. Treatment continued until week 72 or 73, and patients continue to be assessed every 26 weeks, for a minimum of 3 years.

Patient characteristics

Dr Platzbecker said baseline demographic and disease characteristics were generally similar between the treatment arms. All patients were Caucasian, and about 55% were male. The median age was 74 (range, 67-79). About half of patients in each treatment arm belonged to the low-risk IPSS category.

In both arms, most patients had refractory cytopenia with multilineage dysplasia (38.8% in the placebo arm and 46.4% in the darbepoetin alfa arm). Patients also had refractory anemia with excess blasts-1 (20.4% and 13.4%, respectively), refractory anemia (26.5% and 9.3%), refractory anemia with ring sideroblasts (8.2% and 17.5%), 5q deletion (4.1% and 11.3%), unclassifiable MDS (2.0% and 1.0%), and MDS of an unknown type (0% and 1.0%).

In the 16 weeks before randomization, 58.2% of all patients—53.1% in the placebo arm and 60.8% in the darbepoetin alfa arm—did not have any RBC transfusions. About 25% (24.7%)—22.4% in the placebo arm and 25.8% in the darbepoetin alfa arm—received 1 to 3 RBC units. And 17.1%—24.5% in the placebo arm and 13.4% in the darbepoetin alfa arm—received 4 or more RBC units.

Dosing

During the 24-week double-blind period of the study, 77% (37/48) of patients in the placebo arm and 79% (77/98) in the darbepoetin alfa arm received all 8 doses of treatment.

Sixteen percent (n=16) of patients in the darbepoetin alfa arm had a single dose reduction, and 2% (n=2) had 2 dose reductions. None of the patients in the placebo arm had a dose reduction.

Eleven percent of patients in the darbepoetin alfa arm had doses withheld due to increased hemoglobin. The dose was withheld once for 6 patients, twice for 4 patients, and 3 times for 1 patient. None of the placebo-treated patients had a dose withheld for this reason.

Ten percent (n=5) of placebo-treated patients and 2% (n=2) of darbepoetin alfa-treated patients had a dose withheld due to an AE. Two percent (n=1) and 3% (n=3) of patients, respectively, had a dose withheld for “other” reasons (noncompliance, investigator decision, and no investigational product on site).

During the 48-week open-label period of the study, 81% (102/126) of patients who received darbepoetin alfa increased their dose frequency from every 3 weeks to every 2 weeks. Dr Platzbecker said this suggests the optimal dose of the drug was not achieved during the 24-week double-blind period of the study.

Efficacy

During the 24-week double-blind period, there was a significant difference between the treatment arms with regard to RBC transfusions. The transfusion incidence was 59.2% (29/49) in the placebo arm and 36.1% (35/97) in the darbepoetin alfa arm (P=0.008).

During the 48-week open-label period, the incidence of RBC transfusion was 50.8% (64/126) among patients receiving darbepoetin alfa.

During the 24-week double-blind period, 11 patients (14.7%) in the darbepoetin alfa arm had an erythroid hematologic improvement (HI-E), but none of the patients in the placebo arm had such an improvement.

All 11 patients with HI-E had a baseline serum erythropoietin level less than 100 mU/mL, 1 of the patients had 2 RBC units transfused in the 16 weeks prior to randomization, but none had transfusions in the 8 weeks prior to randomization. Four of the patients had a dose withheld due to having hemoglobin levels greater than 12 g/dL.

During the 48-week open-label period, the HI-E rate was 34.7% (34/98) among patients receiving darbepoetin alfa.

Dr Platzbecker said the nature of the HI-E criteria likely underestimated the clinical benefit of darbepoetin alfa in this trial, and this was further complicated by the trial design. Specifically, hemoglobin was measured every 3 weeks, some patients may have had their doses reduced even if they were still anemic, and the optimal dose of darbepoetin alfa was likely not given during the double-blind period (as evidenced by the increase in doses during the open-label period).

For these reasons, Dr Platzbecker and his colleagues are exploring alternative response analyses to determine if there were additional patients who received a clinical benefit from darbepoetin alfa but did not meet HI-E criteria.

Safety

During the 24-week double-blind period, 4.2% (n=2) of patients in the placebo arm and 3.1% (n=3) in the darbepoetin alfa arm had AEs that led to treatment discontinuation. In the placebo arm, these events were pulmonary hypertension and renal failure. In the darbepoetin alfa arm, the events were pulmonary thrombosis, thrombocytopenia, and increased blast cell count.

The incidence of grade 3 or higher AEs was 27.1% (n=13) in the placebo arm and 15.3% (n=15) in the darbepoetin alfa arm. The incidence of grade 4 or higher AEs was 12.5% (n=6) and 5.1% (n=5), respectively. And the incidence of serious AEs was 16.7% (n=8) and 11.2% (n=11), respectively.

The incidence of fatal AEs was 4.2% (n=2) and 1% (n=1), respectively, but none of these were treatment-related. The deaths in the placebo arm were due to cardiac failure and cerebral hemorrhage, while the death in the darbepoetin alfa arm was due to hemorrhagic proctitis.

One patient in the darbepoetin alfa arm experienced a treatment-related serious AE.

AEs occurring at least 5% more frequently in the darbepoetin alfa arm than the placebo arm were fatigue (17.3% and 8.3%), pyrexia (9.2% and 2.1%), headache (7.1% and 2.1%), and myalgia (5.1% and 0%).

During the 48-week double-blind period, 7.9% (n=3) of patients formerly in the placebo arm and 3.4% (n=3) of patients formerly in the darbepoetin alfa arm had AEs that led to treatment discontinuation.

The incidence of grade 3 or higher AEs was 23.7% (n=9) and 31.0% (n=27), respectively. The incidence of grade 4 or higher AEs was 10.5% (n=4) and 10.3% (n=9), respectively. And the incidence of serious AEs was 18.4% (n=7) and 25.3% (n=22), respectively.

The incidence of fatal AEs was 2.6% (n=1) and 1.1% (n=1), respectively, but none of these were treatment-related. Two patients experienced a treatment-related serious AE—1 from each of the former treatment arms.

Uwe Platzbecker, MD

COPENHAGEN—The erythropoiesis-stimulating agent (ESA) darbepoetin alfa can provide a clinical benefit in patients with lower-risk myelodysplastic syndromes (MDS), a phase 3 trial suggests.

In the ARCADE trial, darbepoetin alfa significantly reduced the incidence of red blood cell (RBC) transfusions in patients with low- and intermediate-1 risk myelodysplastic syndrome (MDS), when compared to placebo.

The ESA also significantly improved erythroid response.

In addition, researchers said adverse events (AEs) were generally balanced between the darbepoetin alfa and placebo arms.

Uwe Platzbecker, MD, of University Hospital Carl Gustav Carus Dresden in Germany, presented these results at the 21st Congress of the European Hematology Association (abstract S128). The ARCADE trial was sponsored by Amgen.

Dr Platzbecker noted that, although ESAs are recommended in clinical guidelines to treat anemia in patients with lower-risk MDS, the drugs are not widely approved for this indication.

So, in the ARCADE trial, he and his colleagues assessed darbepoetin alfa in patients with low- or intermediate-1 risk MDS who had not previously taken ESAs or biologic response modifiers.

The patients had hemoglobin levels ≤10 g/dL, endogenous erythropoietin levels ≤500 mU/mL, and low transfusion burden (<4 RBC units in each of 2 consecutive 8-week periods prior to randomization).

During a 24-week period, 147 patients received either darbepoetin alfa at 500 μg (n=97) or placebo (n=49) every 3 weeks. The ESA dose was withheld if patients’ hemoglobin was >12.0 g/dL and decreased if hemoglobin increased by >1.5 g/dL in 3 weeks without transfusion.

At week 25, when the primary and key secondary endpoints were assessed, patients underwent an end-of-treatment period visit. They could then enter a 48-week active treatment period and cross over to receive darbepoetin alfa, with dose escalation allowed beginning on week 31. Treatment continued until week 72 or 73, and patients continue to be assessed every 26 weeks, for a minimum of 3 years.

Patient characteristics

Dr Platzbecker said baseline demographic and disease characteristics were generally similar between the treatment arms. All patients were Caucasian, and about 55% were male. The median age was 74 (range, 67-79). About half of patients in each treatment arm belonged to the low-risk IPSS category.

In both arms, most patients had refractory cytopenia with multilineage dysplasia (38.8% in the placebo arm and 46.4% in the darbepoetin alfa arm). Patients also had refractory anemia with excess blasts-1 (20.4% and 13.4%, respectively), refractory anemia (26.5% and 9.3%), refractory anemia with ring sideroblasts (8.2% and 17.5%), 5q deletion (4.1% and 11.3%), unclassifiable MDS (2.0% and 1.0%), and MDS of an unknown type (0% and 1.0%).

In the 16 weeks before randomization, 58.2% of all patients—53.1% in the placebo arm and 60.8% in the darbepoetin alfa arm—did not have any RBC transfusions. About 25% (24.7%)—22.4% in the placebo arm and 25.8% in the darbepoetin alfa arm—received 1 to 3 RBC units. And 17.1%—24.5% in the placebo arm and 13.4% in the darbepoetin alfa arm—received 4 or more RBC units.

Dosing

During the 24-week double-blind period of the study, 77% (37/48) of patients in the placebo arm and 79% (77/98) in the darbepoetin alfa arm received all 8 doses of treatment.

Sixteen percent (n=16) of patients in the darbepoetin alfa arm had a single dose reduction, and 2% (n=2) had 2 dose reductions. None of the patients in the placebo arm had a dose reduction.

Eleven percent of patients in the darbepoetin alfa arm had doses withheld due to increased hemoglobin. The dose was withheld once for 6 patients, twice for 4 patients, and 3 times for 1 patient. None of the placebo-treated patients had a dose withheld for this reason.

Ten percent (n=5) of placebo-treated patients and 2% (n=2) of darbepoetin alfa-treated patients had a dose withheld due to an AE. Two percent (n=1) and 3% (n=3) of patients, respectively, had a dose withheld for “other” reasons (noncompliance, investigator decision, and no investigational product on site).

During the 48-week open-label period of the study, 81% (102/126) of patients who received darbepoetin alfa increased their dose frequency from every 3 weeks to every 2 weeks. Dr Platzbecker said this suggests the optimal dose of the drug was not achieved during the 24-week double-blind period of the study.

Efficacy

During the 24-week double-blind period, there was a significant difference between the treatment arms with regard to RBC transfusions. The transfusion incidence was 59.2% (29/49) in the placebo arm and 36.1% (35/97) in the darbepoetin alfa arm (P=0.008).

During the 48-week open-label period, the incidence of RBC transfusion was 50.8% (64/126) among patients receiving darbepoetin alfa.

During the 24-week double-blind period, 11 patients (14.7%) in the darbepoetin alfa arm had an erythroid hematologic improvement (HI-E), but none of the patients in the placebo arm had such an improvement.

All 11 patients with HI-E had a baseline serum erythropoietin level less than 100 mU/mL, 1 of the patients had 2 RBC units transfused in the 16 weeks prior to randomization, but none had transfusions in the 8 weeks prior to randomization. Four of the patients had a dose withheld due to having hemoglobin levels greater than 12 g/dL.

During the 48-week open-label period, the HI-E rate was 34.7% (34/98) among patients receiving darbepoetin alfa.

Dr Platzbecker said the nature of the HI-E criteria likely underestimated the clinical benefit of darbepoetin alfa in this trial, and this was further complicated by the trial design. Specifically, hemoglobin was measured every 3 weeks, some patients may have had their doses reduced even if they were still anemic, and the optimal dose of darbepoetin alfa was likely not given during the double-blind period (as evidenced by the increase in doses during the open-label period).

For these reasons, Dr Platzbecker and his colleagues are exploring alternative response analyses to determine if there were additional patients who received a clinical benefit from darbepoetin alfa but did not meet HI-E criteria.

Safety

During the 24-week double-blind period, 4.2% (n=2) of patients in the placebo arm and 3.1% (n=3) in the darbepoetin alfa arm had AEs that led to treatment discontinuation. In the placebo arm, these events were pulmonary hypertension and renal failure. In the darbepoetin alfa arm, the events were pulmonary thrombosis, thrombocytopenia, and increased blast cell count.

The incidence of grade 3 or higher AEs was 27.1% (n=13) in the placebo arm and 15.3% (n=15) in the darbepoetin alfa arm. The incidence of grade 4 or higher AEs was 12.5% (n=6) and 5.1% (n=5), respectively. And the incidence of serious AEs was 16.7% (n=8) and 11.2% (n=11), respectively.

The incidence of fatal AEs was 4.2% (n=2) and 1% (n=1), respectively, but none of these were treatment-related. The deaths in the placebo arm were due to cardiac failure and cerebral hemorrhage, while the death in the darbepoetin alfa arm was due to hemorrhagic proctitis.

One patient in the darbepoetin alfa arm experienced a treatment-related serious AE.

AEs occurring at least 5% more frequently in the darbepoetin alfa arm than the placebo arm were fatigue (17.3% and 8.3%), pyrexia (9.2% and 2.1%), headache (7.1% and 2.1%), and myalgia (5.1% and 0%).

During the 48-week double-blind period, 7.9% (n=3) of patients formerly in the placebo arm and 3.4% (n=3) of patients formerly in the darbepoetin alfa arm had AEs that led to treatment discontinuation.

The incidence of grade 3 or higher AEs was 23.7% (n=9) and 31.0% (n=27), respectively. The incidence of grade 4 or higher AEs was 10.5% (n=4) and 10.3% (n=9), respectively. And the incidence of serious AEs was 18.4% (n=7) and 25.3% (n=22), respectively.

The incidence of fatal AEs was 2.6% (n=1) and 1.1% (n=1), respectively, but none of these were treatment-related. Two patients experienced a treatment-related serious AE—1 from each of the former treatment arms.

Uwe Platzbecker, MD

COPENHAGEN—The erythropoiesis-stimulating agent (ESA) darbepoetin alfa can provide a clinical benefit in patients with lower-risk myelodysplastic syndromes (MDS), a phase 3 trial suggests.

In the ARCADE trial, darbepoetin alfa significantly reduced the incidence of red blood cell (RBC) transfusions in patients with low- and intermediate-1 risk myelodysplastic syndrome (MDS), when compared to placebo.

The ESA also significantly improved erythroid response.

In addition, researchers said adverse events (AEs) were generally balanced between the darbepoetin alfa and placebo arms.

Uwe Platzbecker, MD, of University Hospital Carl Gustav Carus Dresden in Germany, presented these results at the 21st Congress of the European Hematology Association (abstract S128). The ARCADE trial was sponsored by Amgen.

Dr Platzbecker noted that, although ESAs are recommended in clinical guidelines to treat anemia in patients with lower-risk MDS, the drugs are not widely approved for this indication.

So, in the ARCADE trial, he and his colleagues assessed darbepoetin alfa in patients with low- or intermediate-1 risk MDS who had not previously taken ESAs or biologic response modifiers.

The patients had hemoglobin levels ≤10 g/dL, endogenous erythropoietin levels ≤500 mU/mL, and low transfusion burden (<4 RBC units in each of 2 consecutive 8-week periods prior to randomization).

During a 24-week period, 147 patients received either darbepoetin alfa at 500 μg (n=97) or placebo (n=49) every 3 weeks. The ESA dose was withheld if patients’ hemoglobin was >12.0 g/dL and decreased if hemoglobin increased by >1.5 g/dL in 3 weeks without transfusion.

At week 25, when the primary and key secondary endpoints were assessed, patients underwent an end-of-treatment period visit. They could then enter a 48-week active treatment period and cross over to receive darbepoetin alfa, with dose escalation allowed beginning on week 31. Treatment continued until week 72 or 73, and patients continue to be assessed every 26 weeks, for a minimum of 3 years.

Patient characteristics

Dr Platzbecker said baseline demographic and disease characteristics were generally similar between the treatment arms. All patients were Caucasian, and about 55% were male. The median age was 74 (range, 67-79). About half of patients in each treatment arm belonged to the low-risk IPSS category.

In both arms, most patients had refractory cytopenia with multilineage dysplasia (38.8% in the placebo arm and 46.4% in the darbepoetin alfa arm). Patients also had refractory anemia with excess blasts-1 (20.4% and 13.4%, respectively), refractory anemia (26.5% and 9.3%), refractory anemia with ring sideroblasts (8.2% and 17.5%), 5q deletion (4.1% and 11.3%), unclassifiable MDS (2.0% and 1.0%), and MDS of an unknown type (0% and 1.0%).

In the 16 weeks before randomization, 58.2% of all patients—53.1% in the placebo arm and 60.8% in the darbepoetin alfa arm—did not have any RBC transfusions. About 25% (24.7%)—22.4% in the placebo arm and 25.8% in the darbepoetin alfa arm—received 1 to 3 RBC units. And 17.1%—24.5% in the placebo arm and 13.4% in the darbepoetin alfa arm—received 4 or more RBC units.

Dosing

During the 24-week double-blind period of the study, 77% (37/48) of patients in the placebo arm and 79% (77/98) in the darbepoetin alfa arm received all 8 doses of treatment.

Sixteen percent (n=16) of patients in the darbepoetin alfa arm had a single dose reduction, and 2% (n=2) had 2 dose reductions. None of the patients in the placebo arm had a dose reduction.

Eleven percent of patients in the darbepoetin alfa arm had doses withheld due to increased hemoglobin. The dose was withheld once for 6 patients, twice for 4 patients, and 3 times for 1 patient. None of the placebo-treated patients had a dose withheld for this reason.

Ten percent (n=5) of placebo-treated patients and 2% (n=2) of darbepoetin alfa-treated patients had a dose withheld due to an AE. Two percent (n=1) and 3% (n=3) of patients, respectively, had a dose withheld for “other” reasons (noncompliance, investigator decision, and no investigational product on site).

During the 48-week open-label period of the study, 81% (102/126) of patients who received darbepoetin alfa increased their dose frequency from every 3 weeks to every 2 weeks. Dr Platzbecker said this suggests the optimal dose of the drug was not achieved during the 24-week double-blind period of the study.

Efficacy

During the 24-week double-blind period, there was a significant difference between the treatment arms with regard to RBC transfusions. The transfusion incidence was 59.2% (29/49) in the placebo arm and 36.1% (35/97) in the darbepoetin alfa arm (P=0.008).

During the 48-week open-label period, the incidence of RBC transfusion was 50.8% (64/126) among patients receiving darbepoetin alfa.

During the 24-week double-blind period, 11 patients (14.7%) in the darbepoetin alfa arm had an erythroid hematologic improvement (HI-E), but none of the patients in the placebo arm had such an improvement.

All 11 patients with HI-E had a baseline serum erythropoietin level less than 100 mU/mL, 1 of the patients had 2 RBC units transfused in the 16 weeks prior to randomization, but none had transfusions in the 8 weeks prior to randomization. Four of the patients had a dose withheld due to having hemoglobin levels greater than 12 g/dL.

During the 48-week open-label period, the HI-E rate was 34.7% (34/98) among patients receiving darbepoetin alfa.

Dr Platzbecker said the nature of the HI-E criteria likely underestimated the clinical benefit of darbepoetin alfa in this trial, and this was further complicated by the trial design. Specifically, hemoglobin was measured every 3 weeks, some patients may have had their doses reduced even if they were still anemic, and the optimal dose of darbepoetin alfa was likely not given during the double-blind period (as evidenced by the increase in doses during the open-label period).

For these reasons, Dr Platzbecker and his colleagues are exploring alternative response analyses to determine if there were additional patients who received a clinical benefit from darbepoetin alfa but did not meet HI-E criteria.

Safety

During the 24-week double-blind period, 4.2% (n=2) of patients in the placebo arm and 3.1% (n=3) in the darbepoetin alfa arm had AEs that led to treatment discontinuation. In the placebo arm, these events were pulmonary hypertension and renal failure. In the darbepoetin alfa arm, the events were pulmonary thrombosis, thrombocytopenia, and increased blast cell count.

The incidence of grade 3 or higher AEs was 27.1% (n=13) in the placebo arm and 15.3% (n=15) in the darbepoetin alfa arm. The incidence of grade 4 or higher AEs was 12.5% (n=6) and 5.1% (n=5), respectively. And the incidence of serious AEs was 16.7% (n=8) and 11.2% (n=11), respectively.

The incidence of fatal AEs was 4.2% (n=2) and 1% (n=1), respectively, but none of these were treatment-related. The deaths in the placebo arm were due to cardiac failure and cerebral hemorrhage, while the death in the darbepoetin alfa arm was due to hemorrhagic proctitis.

One patient in the darbepoetin alfa arm experienced a treatment-related serious AE.

AEs occurring at least 5% more frequently in the darbepoetin alfa arm than the placebo arm were fatigue (17.3% and 8.3%), pyrexia (9.2% and 2.1%), headache (7.1% and 2.1%), and myalgia (5.1% and 0%).

During the 48-week double-blind period, 7.9% (n=3) of patients formerly in the placebo arm and 3.4% (n=3) of patients formerly in the darbepoetin alfa arm had AEs that led to treatment discontinuation.

The incidence of grade 3 or higher AEs was 23.7% (n=9) and 31.0% (n=27), respectively. The incidence of grade 4 or higher AEs was 10.5% (n=4) and 10.3% (n=9), respectively. And the incidence of serious AEs was 18.4% (n=7) and 25.3% (n=22), respectively.

The incidence of fatal AEs was 2.6% (n=1) and 1.1% (n=1), respectively, but none of these were treatment-related. Two patients experienced a treatment-related serious AE—1 from each of the former treatment arms.

Meletios A. Dimopoulos, MD

COPENHAGEN—The combination of daratumumab, lenalidomide, and dexamethasone (DRd) could become a new standard of care for patients with relapsed or refractory multiple myeloma (MM), according to a speaker at the 21st Congress of the European Hematology Association.

In the phase 3 POLLUX study, DRd conferred the highest response rate reported to date in the treatment of relapsed/refractory MM.

DRd also significantly improved progression free survival (PFS) when compared to treatment with lenalidomide and dexamethasone (Rd).

In addition, the safety profile of DRd was manageable and consistent with results observed in previous studies, according to Meletios A. Dimopoulos, MD, of the National and Kapodistrian University of Athens in Greece.

Dr Dimopoulos presented these results at the congress as abstract LB2238. The POLLUX study was funded by Janssen Research & Development, LLC.

Treatment and patients

POLLUX was a randomized, double-blind study that enrolled 569 patients with relapsed or refractory MM. Patients had received 1 or more prior lines of therapy and had progressive disease.

The patients were randomized to receive DRd (n=286) or Rd (n=283). All patients received lenalidomide at 25 mg on days 1-21 of each cycle until disease progression. They also received dexamethasone at 40 mg weekly until disease progression.

Patients in the daratumumab arm also received daratumumab at 16 mg/kg once a week in cycles 1-2, every other week in cycles 3-6, and once every 4 weeks until disease progression.

Dr Dimopoulos noted that patient and disease features were equally distributed between the treatment arms. The median age was 65 in both arms (overall range, 34-89). About half of patients in each arm had ISS stage I disease, and patients were, roughly, a median of 4 years from diagnosis.

In both arms, patients had a median of 1 prior lines of therapy (overall range, 1-11). Roughly 60% of patients in both arms had received a prior transplant, 86% had received a proteasome inhibitor, 55% had received an immunomodulatory agent, 18% had prior lenalidomide, and 44% had received a proteasome inhibitor and an immunomodulatory agent.

Roughly 28% of patients in each arm were refractory to a proteasome inhibitor, and nearly 30% were refractory to their last line of therapy.

Results

At a median follow-up of 13.5 months, about 35% of patients had discontinued treatment—23% in the DRd arm and 47% in the Rd arm.

Reasons for discontinuation included disease progression (14% and 34%, respectively), adverse events (7% and 8%, respectively), non-compliance with study drug (0.4% and 2%, respectively), withdrawal by patient (0.4% and 2%, respectively), physician decision (1% and 0.7%, respectively), and death (0.7% and 0.4%, respectively).

The study’s primary endpoint was PFS. The median PFS has not been reached in the DRd arm and was 18.4 months in the Rd arm. The 12-month PFS was 83% and 60%, respectively, and the 18-month PFS was 78% and 52%, respectively.

“There is an unprecedented improvement of progression-free survival in favor of daratumumab with lenalidomide and dexamethasone, with a hazard ratio of 0.37 [95% CI, 0.27-0.52; P<0.0001], which corresponds to a 63% reduction in the risk of progressive disease or death in favor of DRd,” Dr Dimopoulos said.

He also pointed out that the improvement in PFS for the DRd arm was seen across all patient subgroups, regardless of age, ISS stage, prior treatment, and type of MM.

Furthermore, response rates were significantly higher in the DRd arm than in the Rd arm. The overall response rates were 93% and 76%, respectively (P<0.0001). And the complete response rates were 43% and 19%, respectively (P<0.0001).

“This trial was associated with the highest response ever reported—so far, at least—in the treatment of relapsed/refractory myeloma,” Dr Dimopoulos noted.

The median duration of response was not reached in the DRd arm and was 17.4 months in the Rd arm.

In addition, there was an overall survival advantage with DRd. The 18-month overall survival was 86% in the DRd arm and 76% in the Rd arm. The hazard ratio was 0.64 (95% CI, 0.40-1.01; P=0.0534).

As for safety, the most common hematologic adverse events (in the DRd and Rd arms, respectively) were neutropenia (59% and 43%), anemia (31% and 35%), thrombocytopenia (27% for both), lymphopenia (6% and 5%), and febrile neutropenia (6% and 3%).

The most common non-hematologic adverse events (in the DRd and Rd arms, respectively) were diarrhea (43% and 25%), fatigue (35% and 28%), upper respiratory tract infection (32% and 21%), constipation (29% and 25%), cough (29% and 13%), muscle spasms (26% and 19%), and pneumonia (14% and 13%).

“DRd has a manageable safety profile consistent with the known safety profile of daratumumab or Rd alone,” Dr Dimopoulos said. “And we believe the combination of daratumumab with lenalidomide and dexamethasone potentially represents a new standard of care for myeloma patients after 1 or more prior lines of therapy.”

Meletios A. Dimopoulos, MD

COPENHAGEN—The combination of daratumumab, lenalidomide, and dexamethasone (DRd) could become a new standard of care for patients with relapsed or refractory multiple myeloma (MM), according to a speaker at the 21st Congress of the European Hematology Association.

In the phase 3 POLLUX study, DRd conferred the highest response rate reported to date in the treatment of relapsed/refractory MM.

DRd also significantly improved progression free survival (PFS) when compared to treatment with lenalidomide and dexamethasone (Rd).

In addition, the safety profile of DRd was manageable and consistent with results observed in previous studies, according to Meletios A. Dimopoulos, MD, of the National and Kapodistrian University of Athens in Greece.

Dr Dimopoulos presented these results at the congress as abstract LB2238. The POLLUX study was funded by Janssen Research & Development, LLC.

Treatment and patients

POLLUX was a randomized, double-blind study that enrolled 569 patients with relapsed or refractory MM. Patients had received 1 or more prior lines of therapy and had progressive disease.

The patients were randomized to receive DRd (n=286) or Rd (n=283). All patients received lenalidomide at 25 mg on days 1-21 of each cycle until disease progression. They also received dexamethasone at 40 mg weekly until disease progression.

Patients in the daratumumab arm also received daratumumab at 16 mg/kg once a week in cycles 1-2, every other week in cycles 3-6, and once every 4 weeks until disease progression.

Dr Dimopoulos noted that patient and disease features were equally distributed between the treatment arms. The median age was 65 in both arms (overall range, 34-89). About half of patients in each arm had ISS stage I disease, and patients were, roughly, a median of 4 years from diagnosis.

In both arms, patients had a median of 1 prior lines of therapy (overall range, 1-11). Roughly 60% of patients in both arms had received a prior transplant, 86% had received a proteasome inhibitor, 55% had received an immunomodulatory agent, 18% had prior lenalidomide, and 44% had received a proteasome inhibitor and an immunomodulatory agent.

Roughly 28% of patients in each arm were refractory to a proteasome inhibitor, and nearly 30% were refractory to their last line of therapy.

Results

At a median follow-up of 13.5 months, about 35% of patients had discontinued treatment—23% in the DRd arm and 47% in the Rd arm.

Reasons for discontinuation included disease progression (14% and 34%, respectively), adverse events (7% and 8%, respectively), non-compliance with study drug (0.4% and 2%, respectively), withdrawal by patient (0.4% and 2%, respectively), physician decision (1% and 0.7%, respectively), and death (0.7% and 0.4%, respectively).

The study’s primary endpoint was PFS. The median PFS has not been reached in the DRd arm and was 18.4 months in the Rd arm. The 12-month PFS was 83% and 60%, respectively, and the 18-month PFS was 78% and 52%, respectively.

“There is an unprecedented improvement of progression-free survival in favor of daratumumab with lenalidomide and dexamethasone, with a hazard ratio of 0.37 [95% CI, 0.27-0.52; P<0.0001], which corresponds to a 63% reduction in the risk of progressive disease or death in favor of DRd,” Dr Dimopoulos said.

He also pointed out that the improvement in PFS for the DRd arm was seen across all patient subgroups, regardless of age, ISS stage, prior treatment, and type of MM.

Furthermore, response rates were significantly higher in the DRd arm than in the Rd arm. The overall response rates were 93% and 76%, respectively (P<0.0001). And the complete response rates were 43% and 19%, respectively (P<0.0001).

“This trial was associated with the highest response ever reported—so far, at least—in the treatment of relapsed/refractory myeloma,” Dr Dimopoulos noted.

The median duration of response was not reached in the DRd arm and was 17.4 months in the Rd arm.

In addition, there was an overall survival advantage with DRd. The 18-month overall survival was 86% in the DRd arm and 76% in the Rd arm. The hazard ratio was 0.64 (95% CI, 0.40-1.01; P=0.0534).

As for safety, the most common hematologic adverse events (in the DRd and Rd arms, respectively) were neutropenia (59% and 43%), anemia (31% and 35%), thrombocytopenia (27% for both), lymphopenia (6% and 5%), and febrile neutropenia (6% and 3%).

The most common non-hematologic adverse events (in the DRd and Rd arms, respectively) were diarrhea (43% and 25%), fatigue (35% and 28%), upper respiratory tract infection (32% and 21%), constipation (29% and 25%), cough (29% and 13%), muscle spasms (26% and 19%), and pneumonia (14% and 13%).

“DRd has a manageable safety profile consistent with the known safety profile of daratumumab or Rd alone,” Dr Dimopoulos said. “And we believe the combination of daratumumab with lenalidomide and dexamethasone potentially represents a new standard of care for myeloma patients after 1 or more prior lines of therapy.”

Meletios A. Dimopoulos, MD

COPENHAGEN—The combination of daratumumab, lenalidomide, and dexamethasone (DRd) could become a new standard of care for patients with relapsed or refractory multiple myeloma (MM), according to a speaker at the 21st Congress of the European Hematology Association.

In the phase 3 POLLUX study, DRd conferred the highest response rate reported to date in the treatment of relapsed/refractory MM.

DRd also significantly improved progression free survival (PFS) when compared to treatment with lenalidomide and dexamethasone (Rd).

In addition, the safety profile of DRd was manageable and consistent with results observed in previous studies, according to Meletios A. Dimopoulos, MD, of the National and Kapodistrian University of Athens in Greece.

Dr Dimopoulos presented these results at the congress as abstract LB2238. The POLLUX study was funded by Janssen Research & Development, LLC.

Treatment and patients

POLLUX was a randomized, double-blind study that enrolled 569 patients with relapsed or refractory MM. Patients had received 1 or more prior lines of therapy and had progressive disease.

The patients were randomized to receive DRd (n=286) or Rd (n=283). All patients received lenalidomide at 25 mg on days 1-21 of each cycle until disease progression. They also received dexamethasone at 40 mg weekly until disease progression.

Patients in the daratumumab arm also received daratumumab at 16 mg/kg once a week in cycles 1-2, every other week in cycles 3-6, and once every 4 weeks until disease progression.

Dr Dimopoulos noted that patient and disease features were equally distributed between the treatment arms. The median age was 65 in both arms (overall range, 34-89). About half of patients in each arm had ISS stage I disease, and patients were, roughly, a median of 4 years from diagnosis.

In both arms, patients had a median of 1 prior lines of therapy (overall range, 1-11). Roughly 60% of patients in both arms had received a prior transplant, 86% had received a proteasome inhibitor, 55% had received an immunomodulatory agent, 18% had prior lenalidomide, and 44% had received a proteasome inhibitor and an immunomodulatory agent.

Roughly 28% of patients in each arm were refractory to a proteasome inhibitor, and nearly 30% were refractory to their last line of therapy.

Results

At a median follow-up of 13.5 months, about 35% of patients had discontinued treatment—23% in the DRd arm and 47% in the Rd arm.

Reasons for discontinuation included disease progression (14% and 34%, respectively), adverse events (7% and 8%, respectively), non-compliance with study drug (0.4% and 2%, respectively), withdrawal by patient (0.4% and 2%, respectively), physician decision (1% and 0.7%, respectively), and death (0.7% and 0.4%, respectively).

The study’s primary endpoint was PFS. The median PFS has not been reached in the DRd arm and was 18.4 months in the Rd arm. The 12-month PFS was 83% and 60%, respectively, and the 18-month PFS was 78% and 52%, respectively.

“There is an unprecedented improvement of progression-free survival in favor of daratumumab with lenalidomide and dexamethasone, with a hazard ratio of 0.37 [95% CI, 0.27-0.52; P<0.0001], which corresponds to a 63% reduction in the risk of progressive disease or death in favor of DRd,” Dr Dimopoulos said.

He also pointed out that the improvement in PFS for the DRd arm was seen across all patient subgroups, regardless of age, ISS stage, prior treatment, and type of MM.

Furthermore, response rates were significantly higher in the DRd arm than in the Rd arm. The overall response rates were 93% and 76%, respectively (P<0.0001). And the complete response rates were 43% and 19%, respectively (P<0.0001).

“This trial was associated with the highest response ever reported—so far, at least—in the treatment of relapsed/refractory myeloma,” Dr Dimopoulos noted.

The median duration of response was not reached in the DRd arm and was 17.4 months in the Rd arm.

In addition, there was an overall survival advantage with DRd. The 18-month overall survival was 86% in the DRd arm and 76% in the Rd arm. The hazard ratio was 0.64 (95% CI, 0.40-1.01; P=0.0534).

As for safety, the most common hematologic adverse events (in the DRd and Rd arms, respectively) were neutropenia (59% and 43%), anemia (31% and 35%), thrombocytopenia (27% for both), lymphopenia (6% and 5%), and febrile neutropenia (6% and 3%).

The most common non-hematologic adverse events (in the DRd and Rd arms, respectively) were diarrhea (43% and 25%), fatigue (35% and 28%), upper respiratory tract infection (32% and 21%), constipation (29% and 25%), cough (29% and 13%), muscle spasms (26% and 19%), and pneumonia (14% and 13%).

“DRd has a manageable safety profile consistent with the known safety profile of daratumumab or Rd alone,” Dr Dimopoulos said. “And we believe the combination of daratumumab with lenalidomide and dexamethasone potentially represents a new standard of care for myeloma patients after 1 or more prior lines of therapy.”

Steven Horwitz, MD

Photo by Larry Young

SAN FRANCISCO—A combination treatment regimen can produce durable remissions in patients newly diagnosed with peripheral T-cell lymphoma (PTCL), results of a phase 1 study suggest.

The patients received brentuximab vedotin plus cyclophosphamide, doxorubicin, and prednisolone (BV+CHP). In some cases, this was followed by BV monotherapy.

The estimated 3-year progression-free survival (PFS) for these patients was 52%, and the overall survival (OS) was 80%.

There was a high rate of peripheral neuropathy (73%), but most cases resolved or improved over time.

Steven Horwitz, MD, of Memorial Sloan Kettering Cancer Center in New York, New York, and his colleagues presented these data as a poster at the 8th Annual T-cell Lymphoma Forum. The study was supported by Seattle Genetics and Millennium Pharmaceuticals.

The researchers presented data on 26 patients newly diagnosed with PTCL. Nineteen patients had systemic anaplastic large-cell lymphoma (ALCL; 16 ALK- and 3 ALK+), 2 had PTCL not otherwise specified, 2 had angioimmunoblastic T-cell lymphoma, 2 had adult T-cell leukemia/lymphoma, and 1 had enteropathy-associated T-cell lymphoma.

The patients’ median age was 56 (range, 21-82). Sixty-nine percent of patients had an IPI score of 2 or higher, and 73% had stage III/IV disease.

Treatment

The patients received BV+CHP every 3 weeks for 6 cycles. Those who achieved at least a partial remission could go on to receive up to 10 additional cycles of single-agent BV at 1.8 mg/kg every 3 weeks.

Twenty-three patients (88%) completed all 6 cycles of BV+CHP, and 21 patients (81%) went on to receive BV monotherapy, 11 of whom (42%) received all 10 cycles.

Fifteen patients (58%) discontinued treatment, 3 due to progressive disease, 3 due to investigator decision, 6 due to adverse events, and 3 due to patient decision.

After a median observation period of 38.7 months (range, 4.6 to 44.3), 77% of patients (n=20) remained on study.

Toxicity

The most common adverse events (occurring in at least 30% of patients) were nausea (69%), peripheral sensory neuropathy (69%), diarrhea (62%), fatigue (58%), alopecia (54%), dyspnea (46%), constipation (35%), myalgia (31%), peripheral edema (31%), chills (31%), anemia (31%), insomnia (31%), and febrile neutropenia.

The most common grade 3 or higher adverse events (occurring in at least 10% of patients) were febrile neutropenia (31%), neutropenia (23%), anemia (15%), and pulmonary embolism (12%).

There were 6 adverse events resulting in treatment discontinuation—peripheral sensory neuropathy (n=3), abdominal pain (n=1), asthenia (n=1), and peripheral motor neuropathy (n=1).

Seventy-three percent of patients (19/26) experienced peripheral neuropathy. Thirty-seven percent (n=7) had a complete resolution of neuropathy, and 58% (n=11) had some improvement. The median time to resolution was 1.3 months. Twelve patients (63%) had ongoing neuropathy at last follow-up, but most had grade 1 (n=10).

Response and survival

The objective response rate was 100%, and the complete response rate was 88% (n=23). One patient who had a partial response at the end of combination therapy achieved a complete response after going on to single-agent BV.

Twenty-one of the 26 patients are still alive—15 with ALCL and 6 with other PTCLs. Sixteen patients have not progressed—9 with ALCL and 5 with other PTCLs.

After progression, 5 patients received BV again, and 3 received stem cell transplants (2 allogeneic and 1 autologous).

The estimated 3-year PFS was 52%, and the estimated OS was 80%. The researchers noted that these rates compare favorably with the historical 3-year PFS and OS rates of 30% and 40%, respectively.

Researchers are currently conducting a phase 3 trial comparing BV+CHP with CHOP as frontline treatment of CD30⁺ mature T-cell lymphomas (ECHELON-2, NCT01777152).

Steven Horwitz, MD

Photo by Larry Young

SAN FRANCISCO—A combination treatment regimen can produce durable remissions in patients newly diagnosed with peripheral T-cell lymphoma (PTCL), results of a phase 1 study suggest.

The patients received brentuximab vedotin plus cyclophosphamide, doxorubicin, and prednisolone (BV+CHP). In some cases, this was followed by BV monotherapy.

The estimated 3-year progression-free survival (PFS) for these patients was 52%, and the overall survival (OS) was 80%.

There was a high rate of peripheral neuropathy (73%), but most cases resolved or improved over time.

Steven Horwitz, MD, of Memorial Sloan Kettering Cancer Center in New York, New York, and his colleagues presented these data as a poster at the 8th Annual T-cell Lymphoma Forum. The study was supported by Seattle Genetics and Millennium Pharmaceuticals.

The researchers presented data on 26 patients newly diagnosed with PTCL. Nineteen patients had systemic anaplastic large-cell lymphoma (ALCL; 16 ALK- and 3 ALK+), 2 had PTCL not otherwise specified, 2 had angioimmunoblastic T-cell lymphoma, 2 had adult T-cell leukemia/lymphoma, and 1 had enteropathy-associated T-cell lymphoma.

The patients’ median age was 56 (range, 21-82). Sixty-nine percent of patients had an IPI score of 2 or higher, and 73% had stage III/IV disease.

Treatment

The patients received BV+CHP every 3 weeks for 6 cycles. Those who achieved at least a partial remission could go on to receive up to 10 additional cycles of single-agent BV at 1.8 mg/kg every 3 weeks.

Twenty-three patients (88%) completed all 6 cycles of BV+CHP, and 21 patients (81%) went on to receive BV monotherapy, 11 of whom (42%) received all 10 cycles.

Fifteen patients (58%) discontinued treatment, 3 due to progressive disease, 3 due to investigator decision, 6 due to adverse events, and 3 due to patient decision.

After a median observation period of 38.7 months (range, 4.6 to 44.3), 77% of patients (n=20) remained on study.

Toxicity

The most common adverse events (occurring in at least 30% of patients) were nausea (69%), peripheral sensory neuropathy (69%), diarrhea (62%), fatigue (58%), alopecia (54%), dyspnea (46%), constipation (35%), myalgia (31%), peripheral edema (31%), chills (31%), anemia (31%), insomnia (31%), and febrile neutropenia.

The most common grade 3 or higher adverse events (occurring in at least 10% of patients) were febrile neutropenia (31%), neutropenia (23%), anemia (15%), and pulmonary embolism (12%).

There were 6 adverse events resulting in treatment discontinuation—peripheral sensory neuropathy (n=3), abdominal pain (n=1), asthenia (n=1), and peripheral motor neuropathy (n=1).

Seventy-three percent of patients (19/26) experienced peripheral neuropathy. Thirty-seven percent (n=7) had a complete resolution of neuropathy, and 58% (n=11) had some improvement. The median time to resolution was 1.3 months. Twelve patients (63%) had ongoing neuropathy at last follow-up, but most had grade 1 (n=10).

Response and survival

The objective response rate was 100%, and the complete response rate was 88% (n=23). One patient who had a partial response at the end of combination therapy achieved a complete response after going on to single-agent BV.

Twenty-one of the 26 patients are still alive—15 with ALCL and 6 with other PTCLs. Sixteen patients have not progressed—9 with ALCL and 5 with other PTCLs.

After progression, 5 patients received BV again, and 3 received stem cell transplants (2 allogeneic and 1 autologous).

The estimated 3-year PFS was 52%, and the estimated OS was 80%. The researchers noted that these rates compare favorably with the historical 3-year PFS and OS rates of 30% and 40%, respectively.

Researchers are currently conducting a phase 3 trial comparing BV+CHP with CHOP as frontline treatment of CD30⁺ mature T-cell lymphomas (ECHELON-2, NCT01777152).

Steven Horwitz, MD

Photo by Larry Young

SAN FRANCISCO—A combination treatment regimen can produce durable remissions in patients newly diagnosed with peripheral T-cell lymphoma (PTCL), results of a phase 1 study suggest.

The patients received brentuximab vedotin plus cyclophosphamide, doxorubicin, and prednisolone (BV+CHP). In some cases, this was followed by BV monotherapy.

The estimated 3-year progression-free survival (PFS) for these patients was 52%, and the overall survival (OS) was 80%.

There was a high rate of peripheral neuropathy (73%), but most cases resolved or improved over time.

Steven Horwitz, MD, of Memorial Sloan Kettering Cancer Center in New York, New York, and his colleagues presented these data as a poster at the 8th Annual T-cell Lymphoma Forum. The study was supported by Seattle Genetics and Millennium Pharmaceuticals.

The researchers presented data on 26 patients newly diagnosed with PTCL. Nineteen patients had systemic anaplastic large-cell lymphoma (ALCL; 16 ALK- and 3 ALK+), 2 had PTCL not otherwise specified, 2 had angioimmunoblastic T-cell lymphoma, 2 had adult T-cell leukemia/lymphoma, and 1 had enteropathy-associated T-cell lymphoma.

The patients’ median age was 56 (range, 21-82). Sixty-nine percent of patients had an IPI score of 2 or higher, and 73% had stage III/IV disease.

Treatment

The patients received BV+CHP every 3 weeks for 6 cycles. Those who achieved at least a partial remission could go on to receive up to 10 additional cycles of single-agent BV at 1.8 mg/kg every 3 weeks.

Twenty-three patients (88%) completed all 6 cycles of BV+CHP, and 21 patients (81%) went on to receive BV monotherapy, 11 of whom (42%) received all 10 cycles.

Fifteen patients (58%) discontinued treatment, 3 due to progressive disease, 3 due to investigator decision, 6 due to adverse events, and 3 due to patient decision.

After a median observation period of 38.7 months (range, 4.6 to 44.3), 77% of patients (n=20) remained on study.

Toxicity

The most common adverse events (occurring in at least 30% of patients) were nausea (69%), peripheral sensory neuropathy (69%), diarrhea (62%), fatigue (58%), alopecia (54%), dyspnea (46%), constipation (35%), myalgia (31%), peripheral edema (31%), chills (31%), anemia (31%), insomnia (31%), and febrile neutropenia.

The most common grade 3 or higher adverse events (occurring in at least 10% of patients) were febrile neutropenia (31%), neutropenia (23%), anemia (15%), and pulmonary embolism (12%).

There were 6 adverse events resulting in treatment discontinuation—peripheral sensory neuropathy (n=3), abdominal pain (n=1), asthenia (n=1), and peripheral motor neuropathy (n=1).

Seventy-three percent of patients (19/26) experienced peripheral neuropathy. Thirty-seven percent (n=7) had a complete resolution of neuropathy, and 58% (n=11) had some improvement. The median time to resolution was 1.3 months. Twelve patients (63%) had ongoing neuropathy at last follow-up, but most had grade 1 (n=10).

Response and survival

The objective response rate was 100%, and the complete response rate was 88% (n=23). One patient who had a partial response at the end of combination therapy achieved a complete response after going on to single-agent BV.

Twenty-one of the 26 patients are still alive—15 with ALCL and 6 with other PTCLs. Sixteen patients have not progressed—9 with ALCL and 5 with other PTCLs.

After progression, 5 patients received BV again, and 3 received stem cell transplants (2 allogeneic and 1 autologous).

The estimated 3-year PFS was 52%, and the estimated OS was 80%. The researchers noted that these rates compare favorably with the historical 3-year PFS and OS rates of 30% and 40%, respectively.

Researchers are currently conducting a phase 3 trial comparing BV+CHP with CHOP as frontline treatment of CD30⁺ mature T-cell lymphomas (ECHELON-2, NCT01777152).